Author: "Olivier Lantz" / Topic: 0302 clinical medicine - Searchworks@Jio Institute Digital Library Search Results

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1. A DNA methylation-based liquid biopsy for triple-negative breast cancer

Author: Michael J. Rauh, Christopher R. Mueller, Katrina Cristall, Tatiana Popova, François-Clément Bidard, Marc-Henri Stern, Jean-Yves Pierga, Clara Sebbag, and Olivier Lantz
Subjects: 0301 basic medicine, Cancer Research, Predictive markers, Article, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, medicine, Blood test, Clinical significance, Liquid biopsy, Triple-negative breast cancer, RC254-282, Molecular medicine, medicine.diagnostic_test, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Diagnostic markers, Methylation, Translational research, Amplicon, medicine.disease, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, Biomarker (medicine), business
Abstract: Here, we present a next-generation sequencing (NGS) methylation-based blood test called methylation DETEction of Circulating Tumour DNA (mDETECT) designed for the optimal detection and monitoring of metastatic triple-negative breast cancer (TNBC). Based on a highly multiplexed targeted sequencing approach, this assay incorporates features that offer superior performance and included 53 amplicons from 47 regions. Analysis of a previously characterised cohort of women with metastatic TNBC with limited quantities of plasma (TNBC was quantitative and showed superior performance to an NGS TP53 mutation-based test carried out on the same patients and to the conventional CA15-3 biomarker. mDETECT also functioned well in serum samples from metastatic TNBC patients where it produced an AUC of 0.97 for detection of a tumour with a sensitivity of 93% for a specificity of 100%. An assay for BRCA1 promoter methylation was also incorporated into the mDETECT assay and functioned well but its clinical significance is currently unclear. Clonal Hematopoiesis of Indeterminate Potential was investigated as a source of background in control subjects but was not seen to be significant, though a link to adiposity may be relevant. The mDETECTTNBC assay is a liquid biopsy able to quantitatively detect all TNBC cancers and has the potential to improve the management of patients with this disease.
Published: 2021

2. Immune Profiling Enables Stratification of Patients With Active Tuberculosis Disease or Mycobacteriu m tuberculosis Infection

Author: Françoise Dromer, Antonio Rausell, Elizabeth Filander, Bruno Charbit, Odile Gelpi, Kalla Astrom, Stanislas Pol, Elisa Nemes, Vincent Rouilly, Mark Hatherill, Hadn Africa, Humphrey Mulenga, Ana Cumano, Hugo Mouquet, Etienne Patin, Lluis Quintana-Murci, Lungisa Jaxa, Laurent Abel, Milena Hasan, James P. Di Santo, Claude Leclerc, Spencer L. Shorte, Vassili Soumelis, Stéphanie Thomas, Caroline Demangel, Mathilde Touvier, Andrés Alcover, Thomas J. Scriba, Matthew L. Albert, Anavaj Sakuntabhai, Hugues Aschard, Nikaïa Smith, Serge Hercberg, Darragh Duffy, Jost Enninga, Olivier Schwartz, Ivo Gomperts-Boneca, Marie-Noëlle Ungeheuer, Simbarashe Mabwe, Ludovic Deriano, Frédéric Tangy, Gérard Eberl, Sandra Pellegrini, Antoine Toubert, Lars Rogge, Stephanus T. Malherbe, Gerhard Walzl, Michele Tameris, Munyaradzi Musvosvi, Alba Llibre, Benno Schwikowski, Olivier Lantz, Nicole Bilek, Philippe Bousso, Pierre Bruhns, Jacques Fellay, and Eric Tartour
Subjects: 0301 basic medicine, Microbiology (medical), Tuberculosis, Enzyme-Linked Immunosorbent Assay, Disease, Asymptomatic, QuantiFERON, Mycobacterium tuberculosis, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Antigen, Latent Tuberculosis, medicine, Humans, 030212 general & internal medicine, Online only Articles, Whole blood, biology, business.industry, immune profiling, biomarkers, patient stratification, bacterial infections and mycoses, medicine.disease, biology.organism_classification, cytokines, 3. Good health, AcademicSubjects/MED00290, 030104 developmental biology, Infectious Diseases, Cohort, Immunology, medicine.symptom, business, Interferon-gamma Release Tests
Abstract: Background Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection. Methods We hypothesized that TruCulture, an immunomonitoring method for whole-blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from patients with active TB and compared with LTBI donors. Mtb-specific antigens and live bacillus Calmette-Guérin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital enzyme-linked immunosorbent assay (ELISA), as well as Luminex. Results TruCulture showed discrimination of active TB cases from LTBI (P < .0001, AUC = .81) compared with QFT (P = .45, AUC = .56), based on an interferon γ (IFNγ) readout after Mtb antigen (Ag) stimulation. This result was replicated in an independent cohort (AUC = .89). In exploratory analyses, TB stratification could be further improved by the Mtb antigen to BCG IFNγ ratio (P < .0001, AUC = .91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with patients with TB, suggesting the possibility to identify subclinical disease. Conclusions TruCulture offers a next-generation solution for whole-blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection., We tested TruCulture, an immunomonitoring tool, to identify active disease from latent Mtb infection. TruCulture showed improved discrimination of tuberculosis cases from LTBI as compared with QuantiFERON. Tuberculosis stratification could be further improved by the Mtb Ag:BCG IFNγ ratio.
Published: 2020

3. Associations between consumption of dietary fibers and the risk of cardiovascular diseases, cancers, type 2 diabetes, and mortality in the prospective NutriNet-Santé cohort

Author: Elisa Desmetz, Lluis Quintana-Murci, Mathilde Touvier, Léopold Fezeu, Serge Hercberg, Nathalie Druesne-Pecollo, Chantal Julia, Darragh Duffy, Pilar Galan, Mélanie Deschasaux, Paule Latino-Martel, Valentin Partula, Olivier Lantz, Bernard Srour, Stanislas Mondot, Emmanuelle Kesse-Guyot, Eloi Chazelas, Matthew L. Albert, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris Cité (UPCité), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC1428 IGR-CURIE, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), Department of Immunology and Infectious Diseases, Insitro [San Francisco], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), NutriNet-Santé study was supported by the following French public institutions: Ministère de la Santé, Santé Publique France, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Conservatoire National des Arts et Métiers (CNAM) and Université Paris-XIII Nord. The Milieu Intérieur Consortium was supported by French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' Grant ANR-10-LABX-69-01. Valentin Partula was funded by Ph.D. a grant from the Labex Milieu Interieur, and is provided financial support from École doctorale 474 Frontières de l’Innovation en Recherche et Education – Programme Bettencourt., Milieu intérieur, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génomique humaine et évolution, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]
Subjects: Adult, Dietary Fiber, Male, medicine.medical_specialty, Colorectal cancer, prospective cohort, Medicine (miscellaneous), 030209 endocrinology & metabolism, Type 2 diabetes, dietary fibers, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Neoplasms, Internal medicine, Vegetables, cancers, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, 2. Zero hunger, Nutrition and Dietetics, Proportional hazards model, business.industry, Public health, Cancer, Middle Aged, medicine.disease, mortality, cardiovascular diseases, 3. Good health, Diabetes Mellitus, Type 2, Fruit, Cohort, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, type 2 diabetes, business
Abstract: BACKGROUND Mounting evidence, yet with varying levels of proof, suggests that dietary fibers (DFs) may exert a protective role against various chronic diseases, but this might depend on the DF type and source. OBJECTIVES Our objectives were to assess the associations between the intake of DFs of different types [total (TDF), soluble (SF), insoluble (IF)] and from different sources (fruits, vegetables, whole grains, legumes, potatoes and tubers) and the risk of cardiovascular diseases (CVDs), cancer, type 2 diabetes (T2D), and mortality in the large-scale NutriNet-Sante prospective cohort (2009-2019). METHODS Overall, 107,377 participants were included. Usual DF intake was estimated from validated repeated 24-h dietary records over the first 2 y following inclusion in the cohort. Associations between sex-specific quintiles of DF intake and the risk of chronic diseases and mortality were assessed using multiadjusted Cox proportional hazards models. RESULTS T2D risk was inversely associated with TDFs [HR for quintile 5 compared with quintile 1: 0.59 (95% CI: 0.42, 0.82), P-trend
Published: 2020

4. A comprehensive assessment of demographic, environmental, and host genetic associations with gut microbiome diversity in healthy individuals

Author: Christian Hammer, Lluis Quintana-Murci, Allyson L. Byrd, Jacques Fellay, Cécile Alanio, Petar Scepanovic, Valentin Partula, Mathilde Touvier, Olivier Lantz, Stanislas Mondot, Jacob Bergstedt, Etienne Patin, Darragh Duffy, Matthew L. Albert, Flavia Hodel, Ecole Polytechnique Fédérale de Lausanne (EPFL), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Genentech, Inc. [San Francisco], Perelman School of Medicine, University of Pennsylvania [Philadelphia], Lund University [Lund], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Swiss Institute of Bioinformatics [Genève] (SIB), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), This work benefited from the support of the French government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01). It was also supported by a grant from the Swiss National Science Foundation (31003A_175603 to JF)., We would like to thank to all the donors for their contribution to the study. The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker, Paris, France), Andres Alcover (Institut Pasteur, Paris, France), Hugues Aschard (Institut Pasteur, Paris, France), Kalla Astrom (Lund University, Lund, Sweden), Philippe Bousso (Institut Pasteur, Paris, France), Pierre Bruhns (Institut Pasteur, Paris, France), Ana Cumano (Institut Pasteur, Paris, France), Caroline Demangel (Institut Pasteur, Paris, France), Ludovic Deriano (Institut Pasteur, Paris, France), James Di Santo (Institut Pasteur, Paris, France), Françoise Dromer (Institut Pasteur, Paris, France), Darragh Duffy (Institut Pasteur, Paris, France), Gérard Eberl (Institut Pasteur, Paris, France), Jost Enninga (Institut Pasteur, Paris, France), Jacques Fellay (EPFL, Lausanne, Switzerland), Odile Gelpi (Institut Pasteur, Paris, France), Ivo Gomperts-Boneca (Institut Pasteur, Paris, France), Milena Hasan (Institut Pasteur, Paris, France), Serge Hercberg (Université Paris 13, Paris, France), Olivier Lantz (Institut Curie, Paris, France), Claude Leclerc (Institut Pasteur, Paris, France), Hugo Mouquet (Institut Pasteur, Paris, France), Sandra Pellegrini (Institut Pasteur, Paris, France), Stanislas Pol (Hôpital Côchin, Paris, France), Antonio Rausell (INSERM UMR 1163 – Institut Imagine, Paris, France), Lars Rogge (Institut Pasteur, Paris, France), Anavaj Sakuntabhai (Institut Pasteur, Paris, France), Olivier Schwartz (Institut Pasteur, Paris, France), Benno Schwikowski (Institut Pasteur, Paris, France), Spencer Shorte (Institut Pasteur, Paris, France), Vassili Soumelis (Institut Curie, Paris, France), Frédéric Tangy (Institut Pasteur, Paris, France), Eric Tartour (Hôpital Européen George Pompidou, Paris, France), Antoine Toubert (Hôpital Saint-Louis, Paris, France), Mathilde Touvier (Université Paris 13, Paris, France), Marie-Noëlle Ungeheuer (Institut Pasteur, Paris, France), Matthew L. Albert (Roche Genentech, South San Francisco, CA, USA), and Lluis Quintana-Murci (Institut Pasteur, Paris, France). Matthew L. Albert and Lluis Quintana-Murci are the co-coordinators of the consortium. Additional information can be found at http://www.milieuinterieur.fr/en., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR: 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Fellay, Jacques [0000-0002-8240-939X], Apollo - University of Cambridge Repository, and Fellay, Jacques
Subjects: Male, population-structure, imputation, Genome-wide association study, dna, Cohort Studies, Feces, 0302 clinical medicine, GWAS, Gut, 16S rRNA gene sequencing, media_common, milieu-interieur, 0303 health sciences, dynamics, Genomics, Middle Aged, Healthy Volunteers, 3. Good health, 030220 oncology & carcinogenesis, Cohort, Medical genetics, lcsh:QR100-130, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Demographics, Sex ratio, Human, Adult, Microbiology (medical), medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, media_common.quotation_subject, Single-nucleotide polymorphism, Biology, Environment, Microbiology, lcsh:Microbial ecology, Young Adult, 03 medical and health sciences, Genetic variation, medicine, Humans, Microbiome, genome, Life Style, Aged, Demography, 030304 developmental biology, inference, Healthy, Bacteria, Host (biology), Research, Gastrointestinal Microbiome, extraction, 030217 neurology & neurosurgery, Imputation (genetics), Diversity (politics)
Abstract: Background The gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Intérieur Consortium, a total of 1000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20–69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition. Results Among 110 demographic, clinical, and environmental factors, 11 were identified as significantly correlated with α-diversity, ß-diversity, or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between > 5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics. Conclusion In a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals. Trial registration ClinicalTrials.gov identifier NCT01699893
Published: 2019

5. Microbial metabolites control the thymic development of mucosal-associated invariant T cells

Author: Manal Sarkis, Jules Gilet, Kristina Niort, François Legoux, Yara El Morr, Olivier Lantz, Emanuele Procopio, Aurélie Balvay, Ahmed El Marjou, Aurélie Darbois, Frédéric Schmidt, Anne Foussier, Déborah Bellet, Celine Daviaud, Marion Salou, Sylvie Rabot, Bernhard Ryffel, Recherches en cancérologie, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité et cancer (U932), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), and Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV]Life Sciences [q-bio], Receptors, Antigen, T-Cell, Thymus Gland, Mucosal associated invariant T cell, Major histocompatibility complex, medicine.disease_cause, Mucosal-Associated Invariant T Cells, Minor Histocompatibility Antigens, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Escherichia coli, medicine, [CHIM]Chemical Sciences, Animals, Germ-Free Life, Symbiosis, Uracil, Receptor, Lung, ComputingMilieux_MISCELLANEOUS, Ribitol, 030304 developmental biology, Mice, Knockout, Orphan receptor, 0303 health sciences, Mucous Membrane, Multidisciplinary, biology, Escherichia coli Proteins, Histocompatibility Antigens Class I, biology.organism_classification, Gastrointestinal Microbiome, Specific Pathogen-Free Organisms, Cell biology, Mice, Inbred C57BL, Nucleotide Deaminases, biology.protein, Spleen, Bacteria, Sugar Alcohol Dehydrogenases, 030215 immunology
Abstract: Commensals rule the MAITrix Mucosal-associated invariant T (MAIT) cells play an important role in mucosal homeostasis. MAIT cells recognize microbial small molecules presented by the major histocompatibility complex class Ib molecule MR1. MAIT cells are absent in germ-free mice, and the mechanisms by which microbiota control MAIT cell development are unknown (see the Perspective by Oh and Unutmaz). Legoux et al. show that, in mice, development of MAIT cells within the thymus is governed by the bacterial product 5-(2-oxopropylideneamino)-6- d -ribitylaminouracil, which rapidly traffics from the mucosa to the thymus, where it is captured by MR1 and presented to developing MAIT cells. Constantinides et al. report that MAIT cell induction only occurs during a limited, early-life window and requires exposure to defined microbes that produce riboflavin derivatives. Continual interactions between MAIT cells and commensals in the skin modulates tissue repair functions. Together, these papers highlight how the microbiota can direct immune cell development and subsequent function at mucosal sites by secreting compounds that act like self-antigens. Science , this issue p. 494 , p. eaax6624 ; see also p. 419
Published: 2019

6. Molecular mechanisms of lineage decisions in metabolite-specific T cells

Author: Olivier Lantz, François Legoux, Jules Gilet, Karine Bernardeau, Emanuele Procopio, and Klara Echasserieau
Subjects: 0301 basic medicine, Receptors, Antigen, T-Cell, alpha-beta, T cell, Metabolite, Immunology, Cell, Thymus Gland, Lymphocyte Activation, Mucosal-Associated Invariant T Cells, Minor Histocompatibility Antigens, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Signaling Lymphocytic Activation Molecule Family, MHC class I, medicine, Animals, Immunology and Allergy, Cell Lineage, Promyelocytic Leukemia Zinc Finger Protein, Uracil, Transcription factor, Ribitol, Mice, Knockout, Thymocytes, Base Sequence, biology, Sequence Analysis, RNA, Effector, Histocompatibility Antigens Class I, MAIT Cells, Cell Differentiation, Cell biology, Haematopoiesis, Hyaluronan Receptors, 030104 developmental biology, medicine.anatomical_structure, chemistry, biology.protein, 030215 immunology
Abstract: Mucosal-associated invariant T cells (MAIT cells) recognize the microbial metabolite 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) presented by the MHC class Ib molecule, MR1. MAIT cells acquire effector functions during thymic development, but the mechanisms involved are unclear. Here we used single-cell RNA-sequencing to characterize the developmental path of 5-OP-RU-specific thymocytes. In addition to the known MAIT1 and MAIT17 effector subsets selected on bone-marrow-derived hematopoietic cells, we identified 5-OP-RU-specific thymocytes that were selected on thymic epithelial cells and differentiated into CD44− naive T cells. MAIT cell positive selection required signaling through the adapter, SAP, that controlled the expression of the transcription factor, ZBTB16. Pseudotemporal ordering of single cells revealed transcriptional trajectories of 5-OP-RU-specific thymocytes selected on either thymic epithelial cells or hematopoietic cells. The resulting model illustrates T cell lineage decisions. MAIT cells recognize the microbial metabolite 5-OP-RU and are selected on DP thymocytes expressing the MHC class Ib molecule MR1. Lantz and colleagues identify 5-OP-RU-specific thymocytes that are selected on thymic epithelial cells and differentiate into naive T cells.
Published: 2019

7. The T cell receptor (TRA) locus in the rabbit ( Oryctolagus cuniculus ): Genomic features and consequences for invariant T cells

Author: Olivier Lantz, Marie-Paule Lefranc, Pierre Boudinot, Stanislas Mondot, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Saclay (COmUE), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Laboratoire d'Immunologie Clinique, Institut Curie [Paris], Centre National de la Recherche Scientifique (CNRS), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique, Institut National de la Sante et de la Recherche Medicale, Institut Curie, Agence Nationale de la Recherche (ANR) (Blanc (MAIT)), Agence Nationale de la Recherche (ANR) (FishRNAVax), Agence Nationale de la Recherche (ANR) (Labex DCBIOL), Labex Milieu Interieur (ANR Investissement d'avenir), Equipe labellisee de la Ligue Contre le Cancer, Agence Nationale de la Recherche ('Investissements d'Avenir' program) ANR10EQPX03 ANR10INBS0908, Canceropole Ile-de-France, and SiRICCurie program
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Immunology, rabbit, Receptors, Antigen, T-Cell, Locus (genetics), Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, evolution, Animals, Humans, Immunology and Allergy, Receptor, Gene, reproductive and urinary physiology, Repertoire, T-cell receptor, VDJ recombination, Natural killer T cell, Isotype, Molecular biology, Immunity, Innate, 3. Good health, 030104 developmental biology, Genetic Loci, biology.protein, Natural Killer T-Cells, Rabbits, Antibody, TCR, 030215 immunology
Abstract: International audience; The rabbit has been widely used in immunology and infectiology. Rabbit immunoglobulins have been extensively studied, leading to the discovery of their idiotypes, allotypic diversity, and of the diversification of the primary repertoire by hyperconversion. Much less is known about rabbit T cell receptors (TR), especially TRA. This isotype is particularly important for innate-like T cells, which typically express invariant TRA (iTRA). The presence of such cells in the rabbit remains an enigma. Rabbit NKT cells seem to be very rare, and lagomorphs lack MAIT cells. TRAV1, the variable gene expressed in the iTRA of these cells across most mammals, and MR1, the MH1-like receptor that present riboflavin derivatives to MAIT cells, are missing in rabbit. An alternative iTRA has been identified, that may be expressed by new innate-like T cells. To facilitate TRA repertoire analyses in rabbit, we report here a full description of TRA and TRD loci and a subgroup definition based on IMGT® classification. Rabbit TRA rearrangements follow the same temporal pattern that is observed in mouse and human. Rare transcripts expressing TRDV/TRDD/TRDJ rearrangements spliced to TRAC were detected. TRA and TRD genes have been made available in IMGT and IMGT/HighV-QUEST, allowing easy analysis of TRA/TRD RepSeq.
Published: 2019

8. MAIT cells: programmed in the thymus to mediate immunity within tissues

Author: Olivier Lantz and François Legoux
Subjects: 0301 basic medicine, Immunology, MAIT Cells, Bacterial Infections, Thymus Gland, Biology, Lymphocyte Activation, Mucosal-Associated Invariant T Cells, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Mycoses, Mucosal immunology, T-Lymphocyte Subsets, Immunity, In vivo, T cell subset, Animals, Humans, Natural Killer T-Cells, Immunology and Allergy, Immunity, Mucosal, 030215 immunology
Abstract: MAIT cells are an evolutionarily conserved T cell subset recognizing ubiquitous microbial metabolites. Herein, we review recent literature showing that MAIT cells can be divided into type 1 and type 17 subsets, which acquire a tissue resident differentiation program in the thymus and localize in specific tissues. We also discuss the nature and in vivo availability of the different agonist and antagonist MAIT ligands with potential consequences for MAIT cell biology.
Published: 2019

9. IL2/Anti-IL2 Complex Combined with CTLA-4, But Not PD-1, Blockade Rescues Antitumor NK Cell Function by Regulatory T-cell Modulation

Author: Philippe De La Rochere, Ruby Alonso, Olivier Lantz, Pamela Caudana, Anaïs Pinto, Nicolás Gonzalo Núñez, Jordan Denizeau, Eliane Piaggio, Christine Sedlik, and Leticia Laura Niborski
Subjects: 0301 basic medicine, Cancer Research, Regulatory T cell, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Immunology, Cell, chemical and pharmacologic phenomena, Antigen-Antibody Complex, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Mice, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Immune system, Cell Line, Tumor, Tumor Microenvironment, medicine, Animals, CTLA-4 Antigen, Chemistry, Antibodies, Monoclonal, hemic and immune systems, Neoplasms, Experimental, Immunotherapy, Mice, Mutant Strains, Blockade, Killer Cells, Natural, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Drug Resistance, Neoplasm, Cell culture, CTLA-4, 030220 oncology & carcinogenesis, Cancer research, Interleukin-2, Female, CD8, T-Lymphocytes, Cytotoxic
Abstract: High-dose IL2 immunotherapy can induce long-lasting cancer regression but is toxic and insufficiently efficacious. Improvements are obtained with IL2/anti-IL2 complexes (IL2Cx), which redirect IL2 action to CD8+ T and natural killer (NK) cells. Here, we evaluated the efficacy of combining IL2Cx with blockade of inhibitory immune pathways. In an autochthonous lung adenocarcinoma model, we show that the IL2Cx/anti–PD-1 combination increases CD8+ T-cell infiltration of the lung and controls tumor growth. In the B16-OVA model, which is resistant to checkpoint inhibition, combination of IL2Cx with PD-1 or CTLA-4 pathway blockade reverses that resistance. Both combinations work by reinvigorating exhausted intratumoral CD8+ T cells and by increasing the breadth of tumor-specific T-cell responses. However, only the IL2Cx/anti–CTLA-4 combination is able to rescue NK cell antitumor function by modulating intratumoral regulatory T cells. Overall, association of IL2Cx with PD-1 or CTLA-4 pathway blockade acts by different cellular mechanisms, paving the way for the rational design of combinatorial antitumor therapies.
Published: 2019

10. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Author: Lara Gibellini, Sussan Nourshargh, Susanna Cardell, Wlodzimierz Maslinski, Mar Felipo-Benavent, Florian Mair, Hans-Martin Jäck, Lilly Lopez, Klaus Warnatz, John Trowsdale, Diana Ordonez, Marcus Eich, William Hwang, Anne Cooke, Dirk Mielenz, Alberto Orfao, Winfried F. Pickl, Vladimir Benes, Alice Yue, T. Vincent Shankey, Maria Tsoumakidou, Virginia Litwin, Gelo Victoriano Dela Cruz, Andrea Cavani, Sara De Biasi, Larissa Nogueira Almeida, Jonathan J M Landry, Claudia Haftmann, Charlotte Esser, Ana Cumano, Anneke Wilharm, Francesco Dieli, Rudi Beyaert, Alessio Mazzoni, Burkhard Ludewig, Carlo Pucillo, Dirk H. Busch, Joe Trotter, Stipan Jonjić, Marc Veldhoen, Josef Spidlen, Aja M. Rieger, Dieter Adam, Srijit Khan, Todd A. Fehniger, Giuseppe Matarese, Maximilien Evrard, Christian Maueröder, Steffen Schmitt, Kristin A. Hogquist, Barry Moran, Raghavendra Palankar, Markus Feuerer, S Schmid, Susann Rahmig, Amy E. Lovett-Racke, James V. Watson, Megan K. Levings, Susanne Melzer, Dinko Pavlinic, Christopher M. Harpur, Christina Stehle, A. Graham Pockley, Toshinori Nakayama, Attila Tárnok, Juhao Yang, Michael Lohoff, Paulo Vieira, Francisco Sala-de-Oyanguren, Christian Kurts, Anastasia Gangaev, Alfonso Blanco, Hans Scherer, Regine J. Dress, Bruno Silva-Santos, Kiyoshi Takeda, Bimba F. Hoyer, Ilenia Cammarata, Daryl Grummitt, Isabel Panse, Günnur Deniz, Bianka Baying, Friederike Ebner, Esther Schimisky, Leo Hansmann, Thomas Kamradt, Edwin van der Pol, Daniel Scott-Algara, Anna Iannone, Giorgia Alvisi, Sebastian R. Schulz, Francesco Liotta, Irmgard Förster, Beatriz Jávega, Hans-Peter Rahn, Caetano Reis e Sousa, Livius Penter, Xuetao Cao, David P. Sester, Keisuke Goda, Peter Wurst, Iain B. McInnes, Ricardo T. Gazzinelli, Federica Piancone, Gerald Willimsky, Yotam Raz, Pärt Peterson, Wolfgang Fritzsche, Yvonne Samstag, Martin Büscher, Thomas Schüler, Susanne Hartmann, Robert J. Wilkinson, Anna E. S. Brooks, Steven L. C. Ketelaars, Catherine Sautès-Fridman, Anna Rubartelli, Petra Bacher, Katja Kobow, Marco A. Cassatella, Andrea Hauser, Henrik E. Mei, Kilian Schober, Silvia Della Bella, Graham Anderson, Michael D. Ward, Garth Cameron, Sebastian Lunemann, Katharina Kriegsmann, Katarzyna M. Sitnik, Brice Gaudilliere, Chantip Dang-Heine, Marcello Pinti, Paul Klenerman, Frank A. Schildberg, Joana Barros-Martins, Laura G. Rico, Hanlin Zhang, Christian Münz, Thomas Dörner, Jakob Zimmermann, Andrea M. Cooper, Jonni S. Moore, Andreas Diefenbach, Yanling Liu, Wolfgang Bauer, Tobit Steinmetz, Katharina Pracht, Leonard Tan, Peter K. Jani, Alan M. Stall, Petra Hoffmann, Christine S. Falk, Jasmin Knopf, Simon Fillatreau, Hans-Dieter Volk, Luis E. Muñoz, David L. Haviland, William W. Agace, Jonathan Rebhahn, Ljiljana Cvetkovic, Mohamed Trebak, Jordi Petriz, Mario Clerici, Diether J. Recktenwald, Anders Ståhlberg, Tristan Holland, Helen M. McGuire, Sa A. Wang, Christian Kukat, Thomas Kroneis, Laura Cook, Wan Ting Kong, Xin M. Wang, Britta Engelhardt, Pierre Coulie, Genny Del Zotto, Sally A. Quataert, Kata Filkor, Gabriele Multhoff, Bartek Rajwa, Federica Calzetti, Hans Minderman, Cosima T. Baldari, Jens Geginat, Hervé Luche, Gert Van Isterdael, Linda Schadt, Sophia Urbanczyk, Giovanna Borsellino, Liping Yu, Dale I. Godfrey, Achille Anselmo, Rachael C. Walker, Andreas Grützkau, David W. Hedley, Birgit Sawitzki, Silvia Piconese, Maria Yazdanbakhsh, Burkhard Becher, Ramon Bellmas Sanz, Michael Delacher, Hyun-Dong Chang, Immanuel Andrä, Hans-Gustaf Ljunggren, José-Enrique O'Connor, Ahad Khalilnezhad, Sharon Sanderson, Federico Colombo, Götz R. A. Ehrhardt, Inga Sandrock, Enrico Lugli, Christian Bogdan, James B. Wing, Susann Müller, Tomohiro Kurosaki, Derek Davies, Ester B. M. Remmerswaal, Kylie M. Quinn, Christopher A. Hunter, Andreas Radbruch, Timothy P. Bushnell, Anna Erdei, Sabine Adam-Klages, Pascale Eede, Van Duc Dang, Rieke Winkelmann, Thomas Korn, Gemma A. Foulds, Dirk Baumjohann, Matthias Schiemann, Manfred Kopf, Jan Kisielow, Lisa Richter, Jochen Huehn, Gloria Martrus, Alexander Scheffold, Jessica G. Borger, Sidonia B G Eckle, John Bellamy Foster, Anna Katharina Simon, Alicia Wong, Mübeccel Akdis, Gisa Tiegs, Toralf Kaiser, James McCluskey, Anna Vittoria Mattioli, Aaron J. Marshall, Hui-Fern Koay, Eva Orlowski-Oliver, Anja E. Hauser, J. Paul Robinson, Jay K. Kolls, Luca Battistini, Mairi McGrath, Jane L. Grogan, Natalio Garbi, Timothy Tree, Kingston H. G. Mills, Stefan H. E. Kaufmann, Wolfgang Schuh, Ryan R. Brinkman, Tim R. Mosmann, Vincenzo Barnaba, Andreas Dolf, Lorenzo Cosmi, Bo Huang, Andreia C. Lino, Baerbel Keller, René A. W. van Lier, Alexandra J. Corbett, Paul S. Frenette, Pleun Hombrink, Helena Radbruch, Sofie Van Gassen, Olivier Lantz, Lorenzo Moretta, Désirée Kunkel, Kirsten A. Ward-Hartstonge, Armin Saalmüller, Leslie Y. T. Leung, Salvador Vento-Asturias, Paola Lanuti, Alicia Martínez-Romero, Sarah Warth, Zhiyong Poon, Diana Dudziak, Andrea Cossarizza, Kovit Pattanapanyasat, Konrad von Volkmann, Jessica P. Houston, Agnès Lehuen, Andrew Filby, Pratip K. Chattopadhyay, Stefano Casola, Annika Wiedemann, Hannes Stockinger, Jürgen Ruland, Arturo Zychlinsky, Claudia Waskow, Katrin Neumann, Ari Waisman, Lucienne Chatenoud, Sudipto Bari, Kamran Ghoreschi, David W. Galbraith, Yvan Saeys, Hamida Hammad, Andrea Gori, Miguel López-Botet, Gabriel Núñez, Sabine Ivison, Michael Hundemer, Dorothea Reimer, Mark C. Dessing, Günter J. Hämmerling, Rudolf A. Manz, Tomas Kalina, Jonas Hahn, Holden T. Maecker, Hendy Kristyanto, Martin S. Davey, Henning Ulrich, Michael L. Dustin, Takashi Saito, Yousuke Takahama, Milena Nasi, Johanna Huber, Jürgen Wienands, Paolo Dellabona, Andreas Schlitzer, Michael D. Leipold, Kerstin H. Mair, Christian Peth, Immo Prinz, Chiara Romagnani, José M. González-Navajas, Josephine Schlosser, Marina Saresella, Matthias Edinger, Dirk Brenner, Nicole Baumgarth, Rikard Holmdahl, Fang-Ping Huang, Guadalupe Herrera, Malte Paulsen, Gergely Toldi, Luka Cicin-Sain, Reiner Schulte, Christina E. Zielinski, Thomas Winkler, Christoph Goettlinger, Philip E. Boulais, Jennie H M Yang, Antonio Celada, Heike Kunze-Schumacher, Julia Tornack, Florian Ingelfinger, Jenny Mjösberg, Andy Riddell, Leonie Wegener, Thomas Höfer, Christoph Hess, James P. Di Santo, Anna E. Oja, J. Kühne, Willem van de Veen, Mary Bebawy, Alberto Mantovani, Bart Everts, Giovanna Lombardi, Laura Maggi, Anouk von Borstel, Pia Kvistborg, Elisabetta Traggiai, A Ochel, Nima Aghaeepour, Charles-Antoine Dutertre, Matthieu Allez, Thomas Höllt, Wenjun Ouyang, Regina Stark, Maries van den Broek, Shimon Sakaguchi, Paul K. Wallace, Silvano Sozzani, Francesca LaRosa, Annette Oxenius, Malgorzata J. Podolska, Ivana Marventano, Wilhelm Gerner, Oliver F. Wirz, Britta Frehse, Gevitha Ravichandran, Martin Herrmann, Carl S. Goodyear, Gary Warnes, Helen Ferry, Stefan Frischbutter, Tim R. Radstake, Salomé LeibundGut-Landmann, Yi Zhao, Axel Schulz, Angela Santoni, Pablo Engel, Daniela C. Hernández, Andreas Acs, Cristiano Scottà, Francesco Annunziato, Thomas Weisenburger, Wolfgang Beisker, Sue Chow, Fritz Melchers, Daniel E. Speiser, Immanuel Kwok, Florent Ginhoux, Dominic A. Boardman, Natalie Stanley, Carsten Watzl, Marie Follo, Erik Lubberts, Andreas Krueger, Susanne Ziegler, Göran K. Hansson, David Voehringer, Antonia Niedobitek, Eleni Christakou, Lai Guan Ng, Sabine Baumgart, Nicholas A Gherardin, Antonio Cosma, Orla Maguire, Jolene Bradford, Daniel Schraivogel, Linda Quatrini, Stephen D. Miller, Rheumatology, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Swiss Institute of Allergy and Asthma Research (SIAF), Universität Zürich [Zürich] = University of Zurich (UZH), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Internal Medicine, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-DENOTHE Center, Institute of Clinical Molecular Biology, Kiel University, Department of Life Sciences [Siena, Italy], Università degli Studi di Siena = University of Siena (UNISI), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Dulbecco Telethon Institute/Department of Biology, Caprotec Bioanalytics GmbH, International Occultation Timing Association European Section (IOTA ES), International Occultation Timing Association European Section, European Molecular Biology Laboratory [Heidelberg] (EMBL), VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Fondazione Santa Lucia (IRCCS), Department of Immunology, Chinese Academy of Medical Sciences, FIRC Institute of Molecular Oncology Foundation, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physiopatology and Transplantation, University of Milan (DEPT), University of Milan, Monash University [Clayton], Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institute of Cellular Pathology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Immunology Unit, Dept. of Oncology, DIBIT San Raffaele Scientific Institute, Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biopharmacy [Bruxelles, Belgium] (Institute for Medical Immunology IMI), Université libre de Bruxelles (ULB), Charité Hospital, Humboldt-Universität zu Berlin, Agency for science, technology and research [Singapore] (A*STAR), Laboratory of Molecular Immunology and the Howard Hughes Institute, Rockefeller University [New York], Kennedy Institute of Rheumatology [Oxford, UK], Imperial College London, Theodor Kocher Institute, University of Bern, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] ( IUF), Université Lumière - Lyon 2 (UL2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Edinburgh, Integrative Biology Program [Milano], Istituto Nazionale Genetica Molecolare [Milano] (INGM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Universitat de Barcelona (UB), Rheumatologie, Cell Biology, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department for Internal Medicine 3, Institute for Clinical Immunology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Delft University of Technology (TU Delft), Medical Inflammation Research, Karolinska Institutet [Stockholm], Department of Photonics Engineering [Lyngby], Technical University of Denmark [Lyngby] (DTU), Dpt of Experimental Immunology [Braunschweig], Helmholtz Centre for Infection Research (HZI), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Department of Histology and Embryology, University of Rijeka, Freiburg University Medical Center, Nuffield Dept of Clinical Medicine, University of Oxford [Oxford]-NIHR Biomedical Research Centre, Institute of Integrative Biology, Molecular Biomedicine, Berlin Institute of Health (BIH), Laboratory for Lymphocyte Differentiation, RIKEN Research Center, Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Department of Surgery [Vancouver, BC, Canada] (Child and Family Research Institute), University of British Columbia (UBC)-Child and Family Research Institute [Vancouver, BC, Canada], College of Food Science and Technology [Shangai], Shanghai Ocean University, Institute for Medical Microbiology and Hygiene, University of Marburg, King‘s College London, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brustzentrum Kantonsspital St. Gallen, Immunotechnology Section, Vaccine Research Center, National Institutes of Health [Bethesda] (NIH)-National Institute of Allergy and Infectious Diseases, Heinrich Pette Institute [Hamburg], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Immunology and Cell Biology, Mario Negri Institute, Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation, Institute of Translational Medicine, Klinik für Dermatologie, Venerologie und Allergologie, School of Biochemistry and Immunology, Department of Medicine Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Lipid Laboratory, Università di Genova, Dipartimento di Medicina Sperimentale, Department of Environmental Microbiology, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Department of Radiation Oncology [Munich], Ludwig-Maximilians-Universität München (LMU), Centre de Recherche Publique- Santé, Université du Luxembourg (Uni.lu), William Harvey Research Institute, Barts and the London Medical School, University of Michigan [Ann Arbor], University of Michigan System, Centro de Investigacion del Cancer (CSIC), Universitario de Salamanca, Molecular Pathology [Tartu, Estonia], University of Tartu, Hannover Medical School [Hannover] (MHH), Centre d'Immunologie de Marseille - Luminy (CIML), Monash Biomedicine Discovery Institute, Cytometry Laboratories and School of Veterinary Medicine, Purdue University [West Lafayette], Data Mining and Modelling for Biomedicine [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, RIKEN Research Center for Allergy and Immunology, Osaka University [Osaka], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institute of Medical Immunology [Berlin, Germany], FACS and Array Core Facility, Johannes Gutenberg - Universität Mainz (JGU), Otto-von-Guericke University [Magdeburg] (OVGU), SUPA School of Physics and Astronomy [University of St Andrews], University of St Andrews [Scotland]-Scottish Universities Physics Alliance (SUPA), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), General Pathology and Immunology (GPI), University of Brescia, Université de Lausanne (UNIL), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, Department of Molecular Immunology, Medizinische Universität Wien = Medical University of Vienna, Dept. Pediatric Cardiology, Universität Leipzig [Leipzig], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Cardiovascular Sciences, Albany Medical College, Dept Pathol, Div Immunol, University of Cambridge [UK] (CAM), Department of Information Technology [Gent], Universiteit Gent, Department of Plant Systems Biology, Department of Plant Biotechnology and Genetics, Universiteit Gent = Ghent University [Belgium] (UGENT), Division of Molecular Immunology, Institute for Immunology, Department of Geological Sciences, University of Oregon [Eugene], Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, University of Colorado [Colorado Springs] (UCCS), FACS laboratory, Cancer Research, London, Cancer Research UK, Regeneration in Hematopoiesis and Animal Models of Hematopoiesis, Faculty of Medicine, Dresden University of Technology, Barbara Davis Center for Childhood Diabetes (BDC), University of Colorado Anschutz [Aurora], School of Computer and Electronic Information [Guangxi University], Guangxi University [Nanning], School of Materials Science and Engineering, Nanyang Technological University [Singapour], Max Planck Institute for Infection Biology (MPIIB), Max-Planck-Gesellschaft, Work in the laboratory of Dieter Adam is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Projektnummer 125440785 – SFB 877, Project B2.Petra Hoffmann, Andrea Hauser, and Matthias Edinger thank BD Biosciences®, San José, CA, USA, and SKAN AG, Bale, Switzerland for fruitful cooperation during the development, construction, and installation of the GMP‐compliant cell sorting equipment and the Bavarian Immune Therapy Network (BayImmuNet) for financial support.Edwin van der Pol and Paola Lanuti acknowledge Aleksandra Gąsecka M.D. for excellent experimental support and Dr. Rienk Nieuwland for textual suggestions. This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO‐TTW), research program VENI 15924.Jessica G Borger, Kylie M Quinn, Mairi McGrath, and Regina Stark thank Francesco Siracusa and Patrick Maschmeyer for providing data.Larissa Nogueira Almeida was supported by DFG research grant MA 2273/14‐1. Rudolf A. Manz was supported by the Excellence Cluster 'Inflammation at Interfaces' (EXC 306/2).Susanne Hartmann and Friederike Ebner were supported by the German Research Foundation (GRK 2046).Hans Minderman was supported by NIH R50CA211108.This work was funded by the Deutsche Forschungsgemeinschaft through the grant TRR130 (project P11 and C03) to Thomas H. Winkler.Ramon Bellmàs Sanz, Jenny Kühne, and Christine S. Falk thank Jana Keil and Kerstin Daemen for excellent technical support. The work was funded by the Germany Research Foundation CRC738/B3 (CSF).The work by the Mei laboratory was supported by German Research Foundation Grant ME 3644/5‐1 and TRR130 TP24, the German Rheumatism Research Centre Berlin, European Union Innovative Medicines Initiative ‐ Joint Undertaking ‐ RTCure Grant Agreement 777357, the Else Kröner‐Fresenius‐Foundation, German Federal Ministry of Education and Research e:Med sysINFLAME Program Grant 01ZX1306B and KMU‐innovativ 'InnoCyt', and the Leibniz Science Campus for Chronic Inflammation (http://www.chronische-entzuendung.org).Axel Ronald Schulz, Antonio Cosma, Sabine Baumgart, Brice Gaudilliere, Helen M. McGuire, and Henrik E. Mei thank Michael D. Leipold for critically reading the manuscript.Christian Kukat acknowledges support from the ISAC SRL Emerging Leaders program.John Trowsdale received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant Agreement 695551)., European Project: 7728036(1978), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Firenze = University of Florence (UniFI)-DENOTHE Center, Università degli Studi di Milano = University of Milan (UNIMI), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt University Of Berlin, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] (IUF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universität Heidelberg [Heidelberg] = Heidelberg University, Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), University of Oxford-NIHR Biomedical Research Centre, Universität Bonn = University of Bonn, Università degli Studi di Firenze = University of Florence (UniFI), Università degli studi di Genova = University of Genoa (UniGe), Universidad de Salamanca, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Université de Lausanne = University of Lausanne (UNIL), Universität Leipzig, Universiteit Gent = Ghent University (UGENT), HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., Cossarizza, A., Chang, H. -D., Radbruch, A., Acs, A., Adam, D., Adam-Klages, S., Agace, W. W., Aghaeepour, N., Akdis, M., Allez, M., Almeida, L. N., Alvisi, G., Anderson, G., Andra, I., Annunziato, F., Anselmo, A., Bacher, P., Baldari, C. T., Bari, S., Barnaba, V., Barros-Martins, J., Battistini, L., Bauer, W., Baumgart, S., Baumgarth, N., Baumjohann, D., Baying, B., Bebawy, M., Becher, B., Beisker, W., Benes, V., Beyaert, R., Blanco, A., Boardman, D. A., Bogdan, C., Borger, J. G., Borsellino, G., Boulais, P. E., Bradford, J. A., Brenner, D., Brinkman, R. R., Brooks, A. E. S., Busch, D. H., Buscher, M., Bushnell, T. P., Calzetti, F., Cameron, G., Cammarata, I., Cao, X., Cardell, S. L., Casola, S., Cassatella, M. A., Cavani, A., Celada, A., Chatenoud, L., Chattopadhyay, P. K., Chow, S., Christakou, E., Cicin-Sain, L., Clerici, M., Colombo, F. S., Cook, L., Cooke, A., Cooper, A. M., Corbett, A. J., Cosma, A., Cosmi, L., Coulie, P. G., Cumano, A., Cvetkovic, L., Dang, V. D., Dang-Heine, C., Davey, M. S., Davies, D., De Biasi, S., Del Zotto, G., Dela Cruz, G. V., Delacher, M., Della Bella, S., Dellabona, P., Deniz, G., Dessing, M., Di Santo, J. P., Diefenbach, A., Dieli, F., Dolf, A., Dorner, T., Dress, R. J., Dudziak, D., Dustin, M., Dutertre, C. -A., Ebner, F., Eckle, S. B. G., Edinger, M., Eede, P., Ehrhardt, G. R. A., Eich, M., Engel, P., Engelhardt, B., Erdei, A., Esser, C., Everts, B., Evrard, M., Falk, C. S., Fehniger, T. A., Felipo-Benavent, M., Ferry, H., Feuerer, M., Filby, A., Filkor, K., Fillatreau, S., Follo, M., Forster, I., Foster, J., Foulds, G. A., Frehse, B., Frenette, P. S., Frischbutter, S., Fritzsche, W., Galbraith, D. W., Gangaev, A., Garbi, N., Gaudilliere, B., Gazzinelli, R. T., Geginat, J., Gerner, W., Gherardin, N. A., Ghoreschi, K., Gibellini, L., Ginhoux, F., Goda, K., Godfrey, D. I., Goettlinger, C., Gonzalez-Navajas, J. M., Goodyear, C. S., Gori, A., Grogan, J. L., Grummitt, D., Grutzkau, A., Haftmann, C., Hahn, J., Hammad, H., Hammerling, G., Hansmann, L., Hansson, G., Harpur, C. M., Hartmann, S., Hauser, A., Hauser, A. E., Haviland, D. L., Hedley, D., Hernandez, D. C., Herrera, G., Herrmann, M., Hess, C., Hofer, T., Hoffmann, P., Hogquist, K., Holland, T., Hollt, T., Holmdahl, R., Hombrink, P., Houston, J. P., Hoyer, B. F., Huang, B., Huang, F. -P., Huber, J. E., Huehn, J., Hundemer, M., Hunter, C. A., Hwang, W. Y. K., Iannone, A., Ingelfinger, F., Ivison, S. M., Jack, H. -M., Jani, P. K., Javega, B., Jonjic, S., Kaiser, T., Kalina, T., Kamradt, T., Kaufmann, S. H. E., Keller, B., Ketelaars, S. L. C., Khalilnezhad, A., Khan, S., Kisielow, J., Klenerman, P., Knopf, J., Koay, H. -F., Kobow, K., Kolls, J. K., Kong, W. T., Kopf, M., Korn, T., Kriegsmann, K., Kristyanto, H., Kroneis, T., Krueger, A., Kuhne, J., Kukat, C., Kunkel, D., Kunze-Schumacher, H., Kurosaki, T., Kurts, C., Kvistborg, P., Kwok, I., Landry, J., Lantz, O., Lanuti, P., Larosa, F., Lehuen, A., LeibundGut-Landmann, S., Leipold, M. D., Leung, L. Y. T., Levings, M. K., Lino, A. C., Liotta, F., Litwin, V., Liu, Y., Ljunggren, H. -G., Lohoff, M., Lombardi, G., Lopez, L., Lopez-Botet, M., Lovett-Racke, A. E., Lubberts, E., Luche, H., Ludewig, B., Lugli, E., Lunemann, S., Maecker, H. T., Maggi, L., Maguire, O., Mair, F., Mair, K. H., Mantovani, A., Manz, R. A., Marshall, A. J., Martinez-Romero, A., Martrus, G., Marventano, I., Maslinski, W., Matarese, G., Mattioli, A. V., Maueroder, C., Mazzoni, A., Mccluskey, J., Mcgrath, M., Mcguire, H. M., Mcinnes, I. B., Mei, H. E., Melchers, F., Melzer, S., Mielenz, D., Miller, S. D., Mills, K. H. G., Minderman, H., Mjosberg, J., Moore, J., Moran, B., Moretta, L., Mosmann, T. R., Muller, S., Multhoff, G., Munoz, L. E., Munz, C., Nakayama, T., Nasi, M., Neumann, K., Ng, L. G., Niedobitek, A., Nourshargh, S., Nunez, G., O'Connor, J. -E., Ochel, A., Oja, A., Ordonez, D., Orfao, A., Orlowski-Oliver, E., Ouyang, W., Oxenius, A., Palankar, R., Panse, I., Pattanapanyasat, K., Paulsen, M., Pavlinic, D., Penter, L., Peterson, P., Peth, C., Petriz, J., Piancone, F., Pickl, W. F., Piconese, S., Pinti, M., Pockley, A. G., Podolska, M. J., Poon, Z., Pracht, K., Prinz, I., Pucillo, C. E. M., Quataert, S. A., Quatrini, L., Quinn, K. M., Radbruch, H., Radstake, T. R. D. J., Rahmig, S., Rahn, H. -P., Rajwa, B., Ravichandran, G., Raz, Y., Rebhahn, J. A., Recktenwald, D., Reimer, D., Reis e Sousa, C., Remmerswaal, E. B. M., Richter, L., Rico, L. G., Riddell, A., Rieger, A. M., Robinson, J. P., Romagnani, C., Rubartelli, A., Ruland, J., Saalmuller, A., Saeys, Y., Saito, T., Sakaguchi, S., Sala-de-Oyanguren, F., Samstag, Y., Sanderson, S., Sandrock, I., Santoni, A., Sanz, R. B., Saresella, M., Sautes-Fridman, C., Sawitzki, B., Schadt, L., Scheffold, A., Scherer, H. U., Schiemann, M., Schildberg, F. A., Schimisky, E., Schlitzer, A., Schlosser, J., Schmid, S., Schmitt, S., Schober, K., Schraivogel, D., Schuh, W., Schuler, T., Schulte, R., Schulz, A. R., Schulz, S. R., Scotta, C., Scott-Algara, D., Sester, D. P., Shankey, T. V., Silva-Santos, B., Simon, A. K., Sitnik, K. M., Sozzani, S., Speiser, D. E., Spidlen, J., Stahlberg, A., Stall, A. M., Stanley, N., Stark, R., Stehle, C., Steinmetz, T., Stockinger, H., Takahama, Y., Takeda, K., Tan, L., Tarnok, A., Tiegs, G., Toldi, G., Tornack, J., Traggiai, E., Trebak, M., Tree, T. I. M., Trotter, J., Trowsdale, J., Tsoumakidou, M., Ulrich, H., Urbanczyk, S., van de Veen, W., van den Broek, M., van der Pol, E., Van Gassen, S., Van Isterdael, G., van Lier, R. A. W., Veldhoen, M., Vento-Asturias, S., Vieira, P., Voehringer, D., Volk, H. -D., von Borstel, A., von Volkmann, K., Waisman, A., Walker, R. V., Wallace, P. K., Wang, S. A., Wang, X. M., Ward, M. D., Ward-Hartstonge, K. A., Warnatz, K., Warnes, G., Warth, S., Waskow, C., Watson, J. V., Watzl, C., Wegener, L., Weisenburger, T., Wiedemann, A., Wienands, J., Wilharm, A., Wilkinson, R. J., Willimsky, G., Wing, J. B., Winkelmann, R., Winkler, T. H., Wirz, O. F., Wong, A., Wurst, P., Yang, J. H. M., Yang, J., Yazdanbakhsh, M., Yu, L., Yue, A., Zhang, H., Zhao, Y., Ziegler, S. M., Zielinski, C., Zimmermann, J., Zychlinsky, A., UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GECE - Génétique cellulaire, Netherlands Organization for Scientific Research, German Research Foundation, European Commission, European Research Council, Repositório da Universidade de Lisboa, CCA - Imaging and biomarkers, Experimental Immunology, AII - Infectious diseases, AII - Inflammatory diseases, Biomedical Engineering and Physics, ACS - Atherosclerosis & ischemic syndromes, and Landsteiner Laboratory
Subjects: 0301 basic medicine, Consensus, Immunology, Consensu, Cell Separation, Biology, Article, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Guidelines, Allergy and Immunology, medicine, Cell separation, Immunology and Allergy, Humans, guidelines, flow cytometry, immunology, medicine.diagnostic_test, BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences, Cell sorting, Flow Cytometry, Cell selection, Data science, 3. Good health, 030104 developmental biology, Phenotype, [SDV.IMM]Life Sciences [q-bio]/Immunology, BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti, 030215 immunology, Human
Abstract: All authors: Andrea Cossarizza Hyun‐Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam‐Klages William W. Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T. Baldari Sudipto Bari Vincenzo Barnaba Joana Barros‐Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A. Boardman Christian Bogdan Jessica G. Borger Giovanna Borsellino Philip E. Boulais Jolene A. Bradford Dirk Brenner Ryan R. Brinkman Anna E. S. Brooks Dirk H. Busch Martin Büscher Timothy P. Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L. Cardell Stefano Casola Marco A. Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K. Chattopadhyay Sue Chow Eleni Christakou Luka Čičin‐Šain Mario Clerici Federico S. Colombo Laura Cook Anne Cooke Andrea M. Cooper Alexandra J. Corbett Antonio Cosma Lorenzo Cosmi Pierre G. Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang‐Heine Martin S. Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P. Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J. Dress Diana Dudziak Michael Dustin Charles‐Antoine Dutertre Friederike Ebner Sidonia B. G. Eckle Matthias Edinger Pascale Eede Götz R.A. Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S. Falk Todd A. Fehniger Mar Felipo‐Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A. Foulds Britta Frehse Paul S. Frenette Stefan Frischbutter Wolfgang Fritzsche David W. Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T. Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A. Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I. Godfrey Christoph Goettlinger Jose M. González‐Navajas Carl S. Goodyear Andrea Gori Jane L. Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M. Harpur Susanne Hartmann Andrea Hauser Anja E. Hauser David L. Haviland David Hedley Daniela C. Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P. Houston Bimba F. Hoyer Bo Huang Fang‐Ping Huang Johanna E. Huber Jochen Huehn Michael Hundemer Christopher A. Hunter William Y. K. Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans‐Martin Jäck Peter K. Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H. E. Kaufmann Baerbel Keller Steven L. C. Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui‐Fern Koay Katja Kobow Jay K. Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze‐Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut‐Landmann Michael D. Leipold Leslie Y.T. Leung Megan K. Levings Andreia C. Lino Francesco Liotta Virginia Litwin Yanling Liu Hans‐Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López‐Botet Amy E. Lovett‐Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T. Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H. Mair Alberto Mantovani Rudolf A. Manz Aaron J. Marshall Alicia Martínez‐Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M. McGuire Iain B. McInnes Henrik E. Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D. Miller Kingston H.G. Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R. Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José‐Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski‐Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F. Pickl Silvia Piconese Marcello Pinti A. Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E. M. Pucillo Sally A. Quataert Linda Quatrini Kylie M. Quinn Helena Radbruch Tim R. D. J. Radstake Susann Rahmig Hans‐Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A. Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B.M. Remmerswaal Lisa Richter Laura G. Rico Andy Riddell Aja M. Rieger J. Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala‐de‐Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes‐Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U. Scherer Matthias Schiemann Frank A. Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R. Schulz Cristiano Scottá Daniel Scott‐Algara David P. Sester T. Vincent Shankey Bruno Silva‐Santos Anna Katharina Simon Katarzyna M. Sitnik Silvano Sozzani Daniel E. Speiser Josef Spidlen Anders Stahlberg Alan M. Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I.M. Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A.W. van Lier Marc Veldhoen Salvador Vento‐Asturias Paulo Vieira David Voehringer Hans‐Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V. Walker Paul K. Wallace Sa A. Wang Xin M. Wang Michael D. Ward Kirsten A Ward‐Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V. Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B. Wing Rieke Winkelmann Thomas H. Winkler Oliver F. Wirz Alicia Wong Peter Wurst Jennie H. M. Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky., These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion., This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO-TTW), research program VENI 15924. This work was funded by the Deutsche Forschungsgemeinschaft. European Union Innovative Medicines Initiative - Joint Undertaking - RTCure Grant Agreement 777357 and innovation program (Grant Agreement 695551).
Published: 2019

11. A common transcriptomic program acquired in the thymus defines tissue residency of MAIT and NKT subsets

Author: Anne-Gaëlle Goubet, Jules Gilet, Emanuele Procopio, Aurélie Darbois, Wilfrid Richer, Celine Daviaud, Virginie Premel, Anastasia du Halgouet, Marion Salou, François Legoux, Ruby Alonso, Olivier Lantz, and Laurie Menger
Subjects: Male, 0301 basic medicine, Adoptive cell transfer, Parabiosis, Transgene, Immunology, chemical and pharmacologic phenomena, Mice, Transgenic, Spleen, Thymus Gland, Biology, Article, Transcriptome, Mice, 03 medical and health sciences, 0302 clinical medicine, RAR-related orphan receptor gamma, medicine, Animals, Humans, Immunology and Allergy, Lung, Research Articles, hemic and immune systems, Intercellular Adhesion Molecule-1, Natural killer T cell, Lymphocyte Function-Associated Antigen-1, 030104 developmental biology, medicine.anatomical_structure, Liver, Organ Specificity, Natural Killer T-Cells, Female, 030215 immunology
Abstract: Salou et al. wondered what could differentiate MAIT and NKT cells, if not for TCR specificity. Once split according to RORγt and T-bet–expressing subsets, MAIT and NKT share almost identical transcriptional programs acquired in the thymus, which result in specific tissue residency patterns., Mucosal-associated invariant T (MAIT) cells are abundant T cells with unique specificity for microbial metabolites. MAIT conservation along evolution indicates important functions, but their low frequency in mice has hampered their detailed characterization. Here, we performed the first transcriptomic analysis of murine MAIT cells. MAIT1 (RORγtneg) and MAIT17 (RORγt+) subsets were markedly distinct from mainstream T cells, but quasi-identical to NKT1 and NKT17 subsets. The expression of similar programs was further supported by strong correlations of MAIT and NKT frequencies in various organs. In both mice and humans, MAIT subsets expressed gene signatures associated with tissue residency. Accordingly, parabiosis experiments demonstrated that MAIT and NKT cells are resident in the spleen, liver, and lungs, with LFA1/ICAM1 interactions controlling MAIT1 and NKT1 retention in spleen and liver. The transcriptional program associated with tissue residency was already expressed in thymus, as confirmed by adoptive transfer experiments. Altogether, shared thymic differentiation processes generate “preset” NKT and MAIT subsets with defined effector functions, associated with specific positioning into tissues.
Published: 2018

12. Corrigendum: Unveiling Interindividual Variability of Human Fibroblast Innate Immune Response Using Robust Cell-Based Protocols

Author: Audrey Chansard, Nelly Dubrulle, Mathilde Poujol de Molliens, Pierre B. Falanga, Tharshana Stephen, Milena Hasan, Ger van Zandbergen, Nathalie Aulner, Spencer L. Shorte, Brigitte David-Watine, the Milieu Intérieur Consortium, Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Serge Hercberg, Olivier Lantz, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Trouvier, Marie-Noëlle Ungeheuer, Darragh Duffy, Matthew L. Albert, Lluis Quintana-Murci, BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Institut Pasteur [Paris], Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Paul-Ehrlich-Institute - Federal Institute for Vaccines and Biomedicines (EPI), Institut Pasteur Korea - Institut Pasteur de Corée, Réseau International des Instituts Pasteur (RIIP), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Lipopolysaccharides, 0301 basic medicine, Cell, Gene Expression, Herpesvirus 1, Human, immortalization, NF-κB, 0302 clinical medicine, TLR (Toll like receptors), FACS, innate immunity, human primary cells, HSV-1, cytokines, Angeborene Immunität, Genes, Reporter, Immunology and Allergy, Polylysine, NF-kB, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Original Research, education.field_of_study, Middle Aged, Flow Cytometry, medicine.anatomical_structure, Host-Pathogen Interactions, [SDV.IMM]Life Sciences [q-bio]/Immunology, Biological Assay, Female, Cell activation, Population, Immunology, Context (language use), Computational biology, Biology, Cell Line, 03 medical and health sciences, Immune system, medicine, Humans, education, Fibroblast, Innate immune system, Correction, Fibroblasts, RC581-607, Immunity, Innate, Toll-Like Receptor 3, Toll-Like Receptor 4, Poly I-C, 030104 developmental biology, Biological Variation, Population, TLR3, Immunologic diseases. Allergy, 030217 neurology & neurosurgery, 030215 immunology
Abstract: The LabEx Milieu Interieur (MI) project is a clinical study centered on the detailed characterization of the baseline and induced immune responses in blood samples from 1,000 healthy donors. Analyses of these samples has lay ground for seminal studies on the genetic and environmental determinants of immunologic variance in a healthy cohort population. In the current study we developed in vitro methods enabling standardized quantification of MI-cohort-derived primary fibroblasts responses. Our results show that in vitro human donor cohort fibroblast responses to stimulation by different MAMPs analogs allows to characterize individual donor immune-phenotype variability. The results provide proof-of-concept foundation to a new experimental framework for such studies. A bio-bank of primary fibroblast lines was generated from 323 out of 1,000 healthy individuals selected from the MI-study cohort. To study inter-donor variability of innate immune response in primary human dermal fibroblasts we chose to measure the TLR3 and TLR4 response pathways, both receptors being expressed and previously studied in fibroblasts. We established high-throughput automation compatible methods for standardized primary fibroblast cell activation, using purified MAMPS analogs, poly I:C and LPS that stimulate TLR3 and TLR4 pathways respectively. These results were in turn compared with a stimulation method using infection by HSV-1 virus. Our “Add-only” protocol minimizes high-throughput automation system variability facilitating whole process automation from cell plating through stimulation to recovery of cell supernatants, and fluorescent labeling. Images were acquired automatically by high-throughput acquisition on an automated high-content imaging microscope. Under these methodological conditions standardized image acquisition provided for quantification of cellular responses allowing biological variability to be measured with low system noise and high biological signal fidelity. Optimal for automated analysis of immuno-phenotype of primary human cell responses our method and experimental framework as reported here is highly compatible to high-throughput screening protocols like those necessary for chemo-genomic screening. In context of primary fibroblasts derived from donors enrolled to the MI-clinical-study our results open the way to assert the utility of studying immune-phenotype characteristics relevant to a human clinical cohort.
Published: 2021
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13. Chronic stress physically spares but functionally impairs innate-like invariant T cells

Author: K. L. Summers, Ken Leslie, Anton I. Skaro, S. M. Mansour Haeryfar, Wataru Inoue, Vijay K. Kuchroo, Paula J. Foster, Joshua Choi, Olivier Lantz, Patrick T. Rudak, Vivian C. McAlister, Katie M. Parkins, and Dwayne N. Jackson
Subjects: Cytotoxicity, Immunologic, Male, 0301 basic medicine, Lymphoma, medicine.medical_treatment, Cell, Interleukin-23, Mice, 0302 clinical medicine, Conditional gene knockout, Chronic stress, Neoplasm Metastasis, 050207 economics, Biology (General), Cytotoxicity, Th1-Th2 Balance, innate immunity, Mice, Inbred BALB C, 050208 finance, Liver Neoplasms, 05 social sciences, T-Lymphocytes, Helper-Inducer, habituation, Interleukin-10, Cell biology, 3. Good health, Gene Expression Regulation, Neoplastic, Cytokine, medicine.anatomical_structure, cytotoxicity, Female, Signal Transduction, Programmed cell death, QH301-705.5, MAIT cells, Mice, Transgenic, Biology, Article, Mucosal-Associated Invariant T Cells, General Biochemistry, Genetics and Molecular Biology, Immobilization, 03 medical and health sciences, Immunity, Cell Line, Tumor, 0502 economics and business, medicine, Animals, Humans, Oxidopamine, psychological stress, iNKT cells, Innate immune system, Interleukins, medicine.disease, Immunity, Innate, 030104 developmental biology, Cell culture, Apoptosis, Chronic Disease, Immunology, Natural Killer T-Cells, Corticosterone, Stress, Psychological, 030217 neurology & neurosurgery
Abstract: SUMMARY The deleterious effects of psychological stress on mainstream T lymphocytes are well documented. However, how stress impacts innate-like T cells is unclear. We report that long-term stress surprisingly abrogates both T helper 1 (TH1)- and TH2-type responses orchestrated by invariant natural killer T (iNKT) cells. This is not due to iNKT cell death because these cells are unusually refractory to stress-inflicted apoptosis. Activated iNKT cells in stressed mice exhibit a “split” inflammatory signature and trigger sudden serum interleukin-10 (IL-10), IL-23, and IL-27 spikes. iNKT cell dysregulation is mediated by cell-autonomous glucocorticoid receptor signaling and corrected upon habituation to predictable stressors. Importantly, under stress, iNKT cells fail to potentiate cytotoxicity against lymphoma or to reduce the burden of metastatic melanoma. Finally, stress physically spares mouse mucosa-associated invariant T (MAIT) cells but hinders their TH1-/TH2-type responses. The above findings are corroborated in human peripheral blood and hepatic iNKT/MAIT cell cultures. Our work uncovers a mechanism of stress-induced immunosuppression., In brief Invariant T cells are emergency responders to infection and cancer. Rudak et al. report that psychological stress unusually spares these innate-like T lymphocytes but alters or impairs their cytokine production and cytotoxic and/or antimetastatic capacities through a cell-autonomous, glucocorticoid receptor-dependent mechanism. This may explain certain aspects of stress-induced immunosuppression., Graphical Abstract
Published: 2021

14. Splicing patterns in SF3B1 mutated uveal melanoma generate shared immunogenic tumor-specific neo-epitopes

Author: Alexandre Houy, Jimena Tosello, Ana Ines Lalanne, Pascale Mariani, Jules Gilet, Gaëlle Pierron, Francesca Lucibello, Vanessa Masson, Stephane Dayot, Sophie Gardrat, Marc-Henri Stern, Raymond L. Barnhill, Sebastian Amigorena, Joshua J. Waterfall, Tatiana Popova, Jeremy Bigot, Sophie Piperno-Neumann, Nathalie Cassoux, Paul Gueguen, Samar Alsafadi, Fariba Nemati, Manuel Rodrigues, Olivier Lantz, Olivier Ganier, Damarys Loew, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], CIC1428 IGR-CURIE, Unité de génétique et biologie des cancers (U830), Département de Recherche Translationnelle, Université Paris sciences et lettres (PSL), Laboratoire de Spectrométrie de Masse Protéomique, and AMIGORENA, Sebastian
Subjects: 0301 basic medicine, Effector, Melanoma, [SDV]Life Sciences [q-bio], Biology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Splicing factor, 030104 developmental biology, 0302 clinical medicine, Oncology, Transcription (biology), 030220 oncology & carcinogenesis, RNA splicing, medicine, Cancer research, Cytotoxic T cell, Gene, CD8
Abstract: Disruption of splicing patterns due to mutations of genes coding splicing factors in tumors represents a potential source of tumor neoantigens, which would be both public (shared between patients) and tumor-specific (not expressed in normal tissues). In this study, we show that mutations of the splicing factor SF3B1 in uveal melanoma generate such immunogenic neoantigens. Memory CD8+ T cells specific for these neoantigens are preferentially found in 20% of patients with uveal melanoma bearing SF3B1-mutated tumors. Single-cell analyses of neoepitope-specific T cells from the blood identified large clonal T-cell expansions, with distinct effector transcription patterns. Some of these expanded T-cell receptors are also present in the corresponding tumors. CD8+ T-cell clones specific for the neoepitopes specifically recognize and kill SF3B1-mutated tumor cells, supporting the use of this new family of neoantigens as therapeutic targets. Significance: Mutations of the splicing factor SF3B1 in uveal melanoma generate shared neoantigens that are uniquely expressed by tumor cells, leading to recognition and killing by specific CD8 T cells. Mutations in splicing factors can be sources of new therapeutic strategies applicable to diverse tumors. This article is highlighted in the In This Issue feature, p. 1861
Published: 2021
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15. High seroprevalence but short‐lived immune response to SARS‐CoV‐2 infection in Paris

Author: Pierre Charneau, Philippe Souque, Evelyne Dufour, Marion Gransagne, Stéphane Petres, Ana Ines Lalanne, Thierry Rose, Isabelle Turbiez, François Dejardin, François Anna, Odile Richard-Le Goff, Olivier Helynck, Maude Guillot-Delost, Sophie Goyard, Alexia Savignoni, François-Clément Bidard, Zaineb Choucha, Fabien Nevo, Franck Perez, Delphine Louis, Véronique Gillon, Yves L. Janin, A Gobillion, Nicolas Escriou, Olivier Lantz, Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris]-TheraVectys, Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Curie [Paris], Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Institut Pasteur [Paris], Laboratoire d’innovation : vaccins – Innovation lab : vaccines, Risques cliniques et sécurité en santé des femmes et en santé périnatale (RISCQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Plateforme technologique Production et purification de protéines recombinantes – Production and Purification of Recombinant Proteins Technological Platform (PPR), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Chimie et Biocatalyse, This work was made possible thanks to the financial support obtained through the URGENCE nouveau coronavirus fundraising campaign of Institut Pasteur and the financial support of the Fondation Total. This study was funded in part by a grant from Fondation de France and by Institut Curie Institutional funding. The luciferin synthesis development has been supported by DARRI (ValoExpress 2016-2018). LuLISA development has been supported by IARP Pasteur-Carnot MI (2019-2020)., Institut Pasteur [Paris] (IP)-TheraVectys, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Université Paris-Saclay, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Lassailly-Bondaz, Anne, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: 0301 basic medicine, Male, Time Factors, Antibodies, Viral, SARS‐CoV‐2, MESH: Antibodies, Neutralizing, Serology, 0302 clinical medicine, Seroepidemiologic Studies, Epidemiology, MESH: COVID-19, Immunology and Allergy, 030212 general & internal medicine, Research Articles, MESH: Immunoglobulin G, 0303 health sciences, education.field_of_study, MESH: Paris, 3. Good health, Titer, Research Article|Basic, ELISA, Female, medicine.symptom, Bioluminescence, Adult, MESH: Pandemics, medicine.medical_specialty, Paris, Population, Immunology, Anosmia, Immunity to infection, Biology, Asymptomatic, Virus, 03 medical and health sciences, COVID‐19, Internal medicine, medicine, Humans, Basic, education, Pandemics, 030304 developmental biology, LuLISA, MESH: Seroepidemiologic Studies, MESH: Humans, SARS-CoV-2, business.industry, MESH: Time Factors, COVID-19, MESH: Adult, Ageusia, Antibodies, Neutralizing, MESH: Male, 030104 developmental biology, Immunization, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Immunoglobulin G, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, MESH: Antibodies, Viral, 030215 immunology
Abstract: International audience; Background Although the COVID-19 pandemic peaked in March/April 2020 in France, the prevalence of infection is barely known. Herein, we assessed the serological response against the SARS-CoV-2 virus in a large population working in one institution of the Paris conurbation. We set up two high-throughput and sensitive methods to assess SARS CoV-2 Nucleoprotein and Spike protein-specific IgG response along with a pseudo-neutralization assay in sera. We studied 1847 participants who also answered a web-based survey on clinical symptoms.Methods and Results In May-July 2020, 11% (95% CI: 9.7-12.6) of serums were positive for IgG against the SARS-CoV-2 N and S protein and 9.5% (CI:8.2-11.0) were pseudo-neutralizer. The prevalence of immunization was 11.6% (CI:10.2-13.2) considering positivity in at least one assays. In 5% (CI:3.9-7.1) of RT-qPCR positive individuals, no systemic IgGs were detected. Among immune individuals, 21% had been asymptomatic.Anosmia and ageusia occurred in 52% of the IgG-positive individuals and in 3% of the negative ones. In contrast, 30% of the anosmia-ageusia cases were seronegative suggesting that the true prevalence of infection may reach 16.6%. In sera obtained 4-8 weeks after the first sampling anti-N and anti-S IgG titers and pseudo-neutralization activity declined by 31%, 17% and 53%, respectively with half-life of 35, 87 and 28 days, respectively.Conclusions The population studied being not particularly exposed to SARS-CoV-2 infection is representative of active workers in the Paris conurbation, suggesting that the current epidemiological models may underestimate the true prevalence of infection. The short lifespan of the serological systemic responses hinders retrospective assessment of the epidemic extent.
Published: 2020
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16. MAIT cell development in mice and humans

Author: François Legoux, Marion Salou, Olivier Lantz, CCSD, Accord Elsevier, Immunité et cancer (U932), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Immunology, Receptors, Antigen, T-Cell, Thymus Gland, Biology, Gene Rearrangement, T-Lymphocyte, Mucosal-Associated Invariant T Cells, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Species Specificity, Animals, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Thymocytes, Effector, Cell growth, T-cell receptor, MAIT Cells, Cell Differentiation, Cell function, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, T cell subset, 030215 immunology
Abstract: MAIT cells arise in the thymus following rearrangement of a T cell receptor (TCR) reactive against microbial vitamin B2-derived metabolites presented by the MHC-Ib molecule, MR1. Mechanisms that are conserved in mammals ensure the frequent production of MR1-restricted TCRs and the intra-thymic differentiation of MR1-restricted thymocytes into effector cells. Upon thymic egress and migration into non-lymphoid tissues, additional signals modulate MAIT cell functions according to each local tissue environment. Here, we review the recent progress made towards a better understanding of the establishment of this major immune cell subset.
Published: 2020

17. Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients

Author: Anne Vincent-Salomon, Becher Burkhard, Delphine Loirat, Cyrill Dimitri Anderfuhren, Nicolas Cagnard, Jimena Tosello Boari, Wilfrid Richer, Christine Sedlik, Sophie Viel, Olivier Lantz, Louis Pérol, Xavier Sastre-Garau, Sebastian Amigorena, Nicolás Gonzalo Núñez, Didier Meseure, Rodrigo Nalio Ramos, Eliane Piaggio, Maud Milder, Philippe De La Rochere, Leticia Laura Niborski, Jeremy Bigot, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Zürich [Zürich] = University of Zurich (UZH), Bioinformatics Platform [Paris], Université Paris Descartes - Paris 5 (UPD5), Département de Biologie des Tumeurs, Institut Curie [Paris], Centre d'Investigation Clinique Biothérapie [Paris] (CICBT), Département d'Oncologie Médicale [Paris], Institut Curie [Paris]-Université Paris sciences et lettres (PSL), Department of Biopathology [Vandoeuvre-lès-Nancy], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER-UNICANCER, This work was funded by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Association pour la Recherche sur le Cancer (ARC), the Institut Curie, the Agence Nationale pour la Recherche (ANR Emergence program), the Institut National du Cancer (INCa), IGR-Curie 1428 Clinical Investigation Center, Labex DCBIOL (ANR-10-IDEX-0001-02 PSL and ANR-11-LABX0043), SIRIC (INCa-DGOS-Inserm_12554, projets 2011–2017:INCa-DGOS-Inserm_4654). N.G.N. received a fellowship from Ligue Nationale Contre le Cancer and the University Research Priority Program (URPP)., ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), Bodescot, Myriam, and Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID
Subjects: 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Science, medicine.medical_treatment, General Physics and Astronomy, Cancer immunotherapy, Breast Neoplasms, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, T-Lymphocytes, Regulatory, Article, General Biochemistry, Genetics and Molecular Biology, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, lcsh:Science, Lymph node, Immunosuppression Therapy, Multidisciplinary, business.industry, T-cell receptor, Immunosuppression, hemic and immune systems, General Chemistry, medicine.disease, 3. Good health, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 030104 developmental biology, medicine.anatomical_structure, Lymphatic Metastasis, 030220 oncology & carcinogenesis, B7-1 Antigen, Cancer research, Tumour immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, lcsh:Q, Lymph Nodes, Lymph, business, CD80
Abstract: Tumor-draining lymph node (TDLN) invasion by metastatic cells in breast cancer correlates with poor prognosis and is associated with local immunosuppression, which can be partly mediated by regulatory T cells (Tregs). Here, we study Tregs from matched tumor-invaded and non-invaded TDLNs, and breast tumors. We observe that Treg frequencies increase with nodal invasion, and that Tregs express higher levels of co-inhibitory/stimulatory receptors than effector cells. Also, while Tregs show conserved suppressive function in TDLN and tumor, conventional T cells (Tconvs) in TDLNs proliferate and produce Th1-inflammatory cytokines, but are dysfunctional in the tumor. We describe a common transcriptomic signature shared by Tregs from tumors and nodes, including CD80, which is significantly associated with poor patient survival. TCR RNA-sequencing analysis indicates trafficking between TDLNs and tumors and ongoing Tconv/Treg conversion. Overall, TDLN Tregs are functional and express a distinct pattern of druggable co-receptors, highlighting their potential as targets for cancer immunotherapy., Tumor-draining lymph nodes are often the first site of metastasis in breast cancer patients. Here, the authors show that metastatic lymph nodes are characterized by the accumulation of suppressive regulatory T cells with a distinct phenotype compared to matched non-invaded lymph nodes and tumors.
Published: 2020

18. MAIT Cell Development and Functions: the Microbial Connection

Author: Marion Salou, François Legoux, Olivier Lantz, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and CCSD, Accord Elsevier
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Immunology, Cell, Receptors, Antigen, T-Cell, Biology, Epithelium, Mucosal-Associated Invariant T Cells, 03 medical and health sciences, 0302 clinical medicine, Antigen, medicine, Immunology and Allergy, Animals, Humans, Receptor, ComputingMilieux_MISCELLANEOUS, Bacteria, Cell growth, T-cell receptor, medicine.disease, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Dysbiosis, Homeostasis
Abstract: Summary Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved T cell subset, which reacts to most bacteria through T cell receptor (TCR)-mediated recognition of metabolites derived from the vitamin B2 biosynthetic pathway. Microbiota-derived signals affect all stages of MAIT cell biology including intra-thymic development, peripheral expansion, and functions in specific organs. In tissues, MAIT cells can integrate multiple signals and display effector functions involved in the defense against infectious pathogens. In addition to anti-bacterial activity, MAIT cells improve wound healing in the skin, suggesting a role in epithelium homeostasis through bi-directional interactions with the local microbiota. In humans, blood MAIT cell frequency is modified during several auto-immune diseases, which are often associated with microbiota dysbiosis, further emphasizing the potential interplay of MAIT cells with the microbiota. Here, we will review how microbes interact with MAIT cells, from initial intra-thymic development to tissue colonization and functions.
Published: 2020

19. Peptide–TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens

Author: Richard Laga, Robert A. Seder, Hidehiro Yamane, Nicolas J. Blobel, Yaakov Itzkowitz, Eliane Piaggio, Faezzah Baharom, Vincent L. Coble, Leonard W. Seymour, Brennan Decker, Olivier Lantz, Christine Sedlik, Ramiro A. Ramirez-Valdez, Justin Cheung, Joseph R. Francica, Geoffrey M. Lynn, Neeha Zaidi, Yaling Zhu, Sarah R. Nichols, Joshua D. Bernstock, Mateusz Maciejewski, Andrew S. Ishizuka, Joshua M. Gammon, Jordan Denizeau, Brian Francica, Christopher M. Jewell, Philippe De La Rochere, Charles G. Drake, Kennedy Tobin, Margery G. Smelkinson, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Avidea Technologies, Inc, University of Maryland [Baltimore], Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine [Baltimore], Czech Academy of Sciences [Prague] (CAS), University of Oxford [Oxford], Institut Curie [Paris], Piaggio-Flaiszman, Eliane, Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford, Tempest Therapeutics [San Francisco], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), and Duchange, Nathalie
Subjects: medicine.medical_treatment, [SDV]Life Sciences [q-bio], Melanoma, Experimental, Peptide, CD8-Positive T-Lymphocytes, Applied Microbiology and Biotechnology, Mice, 0302 clinical medicine, Cytotoxic T cell, Precision Medicine, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, 0303 health sciences, biology, integumentary system, Vaccination, 3. Good health, [SDV] Life Sciences [q-bio], Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Adjuvant, Biotechnology, Primates, [SDV.IMM] Life Sciences [q-bio]/Immunology, Biomedical Engineering, Bioengineering, Major histocompatibility complex, Cancer Vaccines, Article, 03 medical and health sciences, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, Antigen, Adjuvants, Immunologic, Immunity, Antigens, Neoplasm, Cell Line, Tumor, medicine, Animals, 030304 developmental biology, Vaccines, Conjugate, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, chemistry, Toll-Like Receptor 7, Cell culture, Toll-Like Receptor 8, biology.protein, Cancer research, Nanoparticles, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, 030217 neurology & neurosurgery
Abstract: International audience; Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.
Published: 2020

20. Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors

Author: Petar Scepanovic, Julie Hunkapiller, Jacob Bergstedt, Alejandra Urrutia, Jacques Fellay, Lluis Quintana-Murci, Hélène Quach, Friederike Jönsson, Cherie Green, Olivier Lantz, Lars Rogge, Stéphanie Thomas, Vincent Rouilly, Barbara Piasecka, Yoong Wearn Lim, Claire Leloup, Cécile Alanio, Isabelle Peguillet, Christian Hammer, Benoit Beitz, Magnus Fontes, Magge Zepeda, Matthew L. Albert, Valentina Libri, James P. Di Santo, Etienne Patin, Milena Hasan, François Huetz, Darragh Duffy, Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Lund University [Lund], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Anticorps en Thérapie et Pathologie, Genentech, Inc. [San Francisco], Immunorégulation, Biologie des Populations Lymphocytaires, Institut Curie [Paris], International Group for Data Analysis (IGDA), Immunité Innée - Innate Immunity, This work benefited from support of the French government’s program ‘Investissement d’Avenir’, managed by the Agence Nationale de la Recherche (reference 10-LABX-69-01). J.B. is a member of the LCCC Linnaeus Center and the ELLIIT Excellence Center at Lund University and is supported by the ELLIIT Excellence Center., The Milieu Intérieur Consortium : Laurent Abel, Andres Alcover, Kalle Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James P. Di Santo, Françoise Dromer, Darragh Duffy, Gérard Eberl, Jost Enninga, Jacques Fellay, Antonio Freitas, Odile Gelpi, Ivo Gomperts Boneca, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Marie-Noëlle Ungeheuer, Lluís Quintana-Murci & Matthew L. Albert, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne (UNIL), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: Adult, Male, 0301 basic medicine, MESH: Immunity, Innate/genetics, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Immunophenotyping, MESH: Genetic Variation/immunology, Immunology, Genome-wide association study, Disease, Adaptive Immunity, Biology, Immunophenotyping, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, Genetic variation, Humans, Immunology and Allergy, Aged, Genetic association, MESH: Aged, Innate immune system, MESH: Humans, MESH: Middle Aged, Genetic Variation, MESH: Adult, Environmental exposure, Middle Aged, Immunity, Innate, MESH: Male, 3. Good health, 030104 developmental biology, MESH: Young Adult, MESH: Genome-Wide Association Study, MESH: Adaptive Immunity/genetics, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Female, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: A Publisher Correction to this article was published on 03 May 2018; International audience; The quantification and characterization of circulating immune cells provide key indicators of human health and disease. To identify the relative effects of environmental and genetic factors on variation in the parameters of innate and adaptive immune cells in homeostatic conditions, we combined standardized flow cytometry of blood leukocytes and genome-wide DNA genotyping of 1,000 healthy, unrelated people of Western European ancestry. We found that smoking, together with age, sex and latent infection with cytomegalovirus, were the main non-genetic factors that affected variation in parameters of human immune cells. Genome-wide association studies of 166 immunophenotypes identified 15 loci that showed enrichment for disease-associated variants. Finally, we demonstrated that the parameters of innate cells were more strongly controlled by genetic variation than were those of adaptive cells, which were driven by mainly environmental exposure. Our data establish a resource that will generate new hypotheses in immunology and highlight the role of innate immunity in susceptibility to common autoimmune diseases.
Published: 2018

21. MAIT cells in infectious diseases

Author: Katarzyna Franciszkiewicz, Marion Salou, and Olivier Lantz
Subjects: 0301 basic medicine, Immunology, Apoptosis, Context (language use), Communicable Diseases, Microbiology, Proinflammatory cytokine, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, T-Lymphocyte Subsets, Animals, Humans, Tuberculosis, Immunology and Allergy, Secretion, biology, Effector, Interleukin-17, Interleukin-18, MAIT Cells, biology.organism_classification, Interleukin-12, In vitro, 030104 developmental biology, Bacteria, 030215 immunology
Abstract: In humans, MAIT cells represent the most abundant T cell subset reacting against bacteria. Their frequency in the blood is decreased in a large variety of infectious diseases of either bacterial or viral origin. MAIT cells accumulate at the site of bacterial infection and are protective in experimental infection models. Recent epidemiological evidence supports an implication of MAIT cells in protecting against tuberculosis. MAIT cells can be activated either through direct recognition of microbial ligands or by inflammatory cytokines such as IL-12 and IL-18. MAIT cells secrete IFN-γ, IL-17 and/or other effector molecules according to the context of triggering. MAIT cells can kill bacterially infected epithelial cells in vitro. Herein, we summarize and discuss the data suggesting a role for MAIT cells in infectious diseases.
Published: 2017

22. Patient-Specific Circulating Tumor DNA Detection during Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

Author: Caroline Hego, Maud Milder, François-Clément Bidard, Jean-Yves Pierga, Aurore Rampanou, Alexandre Houy, Olivier Lantz, Francesca Riva, Marc-Henri Stern, Paul Cottu, Jordan Madic, Marie-Paule Sablin, Anne Vincent-Salomon, Charlotte Proudhon, and Adrien Saliou
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Pathology, Mitotic index, medicine.medical_treatment, Clinical Biochemistry, Triple Negative Breast Neoplasms, Polymerase Chain Reaction, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, Humans, Stage (cooking), Neoadjuvant therapy, Triple-negative breast cancer, Chemotherapy, business.industry, Biochemistry (medical), DNA, Neoplasm, Middle Aged, medicine.disease, Minimal residual disease, Neoadjuvant Therapy, 030104 developmental biology, Tumor progression, 030220 oncology & carcinogenesis, Tumor Suppressor Protein p53, business
Abstract: BACKGROUND In nonmetastatic triple-negative breast cancer (TNBC) patients, we investigated whether circulating tumor DNA (ctDNA) detection can reflect the tumor response to neoadjuvant chemotherapy (NCT) and detect minimal residual disease after surgery. METHODS Ten milliliters of plasma were collected at 4 time points: before NCT; after 1 cycle; before surgery; after surgery. Customized droplet digital PCR (ddPCR) assays were used to track tumor protein p53 (TP53) mutations previously characterized in tumor tissue by massively parallel sequencing (MPS). RESULTS Forty-six patients with nonmetastatic TNBC were enrolled. TP53 mutations were identified in 40 of them. Customized ddPCR probes were validated for 38 patients, with excellent correlation with MPS (r = 0.99), specificity (≥2 droplets/assay), and sensitivity (at least 0.1%). At baseline, ctDNA was detected in 27/36 patients (75%). Its detection was associated with mitotic index (P = 0.003), tumor grade (P = 0.003), and stage (P = 0.03). During treatment, we observed a drop of ctDNA levels in all patients but 1. No patient had detectable ctDNA after surgery. The patient with rising ctDNA levels experienced tumor progression during NCT. Pathological complete response (16/38 patients) was not correlated with ctDNA detection at any time point. ctDNA positivity after 1 cycle of NCT was correlated with shorter disease-free (P < 0.001) and overall (P = 0.006) survival. CONCLUSIONS Customized ctDNA detection by ddPCR achieved a 75% detection rate at baseline. During NCT, ctDNA levels decreased quickly and minimal residual disease was not detected after surgery. However, a slow decrease of ctDNA level during NCT was strongly associated with shorter survival.
Published: 2017

23. A TCR-Dependent Tissue Repair Potential of MAIT Cells

Author: Olivier Lantz, Marion Salou, Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, T cell, [SDV]Life Sciences [q-bio], Immunology, Cell, T-cell receptor, Mucosal associated invariant T cell, Biology, Gene signature, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Transcriptome, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Antigen, medicine, Immunology and Allergy, Receptor, 030215 immunology
Abstract: Three studies published in Cell Reports (Hinks et al., Lamichhane et al., and Leng et al.) describe the transcriptome of human and mouse mucosal-associated invariant T (MAIT) cells after cognate and noncognate stimulation. The results confirm the variability of MAIT cell effector functions and provide evidence of a new tissue-repair gene signature expressed upon T cell receptor (TCR) stimulation.
Published: 2019

24. Pdl1 and icosl discriminate human secretory and helper dendritic cells

Author: Christophe Le Tourneau, Maud Kamal, Maude Guillot-Delost, Jerzy Klijanienko, Caroline Hoffmann, Charlotte Lecerf, Floriane Noel, Aurore Surun, Juliette Rochefort, Olivier Lantz, Vassili Soumelis, Lilith Faucheux, Paula Michea, Philémon Sirven, and Maximilien Grandclaudon
Subjects: 0303 health sciences, Chemokine, CD40, biology, Chemistry, medicine.medical_treatment, T cell, CCL19, Immunotherapy, In vitro, Cell biology, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, biology.protein, Tumor necrosis factor alpha, 030304 developmental biology, 030215 immunology
Abstract: Dendritic cells (DC) are described as immature at the steady state, with a high antigen capture capacity, turning into a mature state with a strong T cell stimulatory capacity upon activation. Using 16 different stimuli in vitro (130 observations), we describe two states of human activated dendritic cells. PDL1highICOSLlow “secretory DC” produced large amounts of inflammatory cytokines and chemokines but induced very low levels of T helper (Th) cytokines following DC-T co-culture; conversely PDL1lowICOSLhigh “helper DC” produced low levels of secreted factors but induced high levels of Th cytokines characteristic of a broad range of Th subsets. Secretory DC were phenotypically identified in T cell inflamed primary head and neck squamous cell carcinoma. RNAseq analysis showed that they expressed a typical secretory DC signature, including CD40, PVR, IL1B, TNF, and CCL19. This novel and universal functional dichotomy of human DC opens broad perspectives for the characterization of inflammatory diseases, and for immunotherapy.
Published: 2019

25. Pre-transplant donor CD4− invariant NKT cell expansion capacity predicts the occurrence of acute graft-versus-host disease

Author: Olivier Lantz, Mohamad Mohty, Etienne Paubelle, Alejandro Palomar Gómez, Trebeden-Nègre H, Marie-Thérèse Rubio, Tereza Coman, Marina Cavazzana, Felipe Suarez, M. Bouillié, David Sibon, Anne C. Brignier, Urien S, Nguyen-Khoc S, Bouazza N, Olivier Hermine, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Instituto de Acuicultura de Torre la Sal, Torre la Sal s/n, Spanish National Research Council (CSIC), Immunité et cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, Université Paris Descartes - Paris 5 (UPD5), Rubio, Marie Therese, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Tarnier, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Cancer Research, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, T cell, CD34, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematopoietic stem cell transplantation, Human leukocyte antigen, invariant NKT cells, Biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, immune system diseases, hemic and lymphatic diseases, graft versus host disease, medicine, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Natural killer T cell, 3. Good health, Transplantation, surgical procedures, operative, 030104 developmental biology, medicine.anatomical_structure, Oncology, Allogeneic hematopoietic stem cell transplantation, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bone marrow, Stem cell, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: International audience; Clinically useful pre-transplant predictive factors of acute graft-versus-host-disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-SCT) are lacking. We prospectively analyzed HSC graft content in CD34+, NK, conventional T, regulatory T and invariant natural killer T (iNKT) cells in 117 adult patients before allo-SCT. Results were correlated with occurrence of aGVHD and relapse. In univariate analysis, iNKT cells were the only graft cell populations associated with occurrence of aGVHD. In multivariate analysis, CD4− iNKT/T cell frequency could predict grade II-IV aGVHD in bone marrow and peripheral blood stem cell (PBSC) grafts, while CD4− iNKT expansion capacity was predictive in PBSC grafts. Receiver operating characteristic analyses determined the CD4− iNKT expansion factor as the best predictive factor of aGVHD. Incidence of grade II-IV aGVHD was reduced in patients receiving a graft with an expansion factor above versus below 6.83 (9.7 vs 80%, P
Published: 2016

26. Circulating tumor DNA for triple-negative breast cancer diagnosis and treatment decisions

Author: Olivier Lantz, Anne Vincent-Salomon, Adrien Saliou, Jean-Yves Pierga, Charlotte Proudhon, Marc-Henri Stern, and François-Clément Bidard
Subjects: 0301 basic medicine, Oncology, CA15-3, medicine.medical_specialty, Triple Negative Breast Neoplasms, Context (language use), Disease, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, Biomarkers, Tumor, Genetics, medicine, Humans, Pathology, Molecular, Liquid biopsy, Molecular Biology, Triple-negative breast cancer, business.industry, DNA, Neoplasm, Neoplastic Cells, Circulating, Prognosis, medicine.disease, 030104 developmental biology, Circulating tumor DNA, 030220 oncology & carcinogenesis, Molecular Medicine, Female, business
Abstract: Triple-negative breast cancer (TNBC) is a highly aggressive disease characterized by a high number of relapses and poor overall survival. The heterogeneity of the disease and the limited treatment options compared to other breast cancer subtypes mainly explain these clinical outcomes. New biomarkers are urgently needed to improve the management of TNBC. Circulating tumor DNA, identified by tumor-related molecular alterations, could be used in the context of non-invasive "liquid biopsy" and help in TNBC diagnosis and treatment decisions. In this review, we discuss the key issues related to the potential of circulating tumor DNA to improve the management of this disease and the future steps to overcome before its implementation into clinical routine within the next 5 years.
Published: 2015

27. Clinical potential of circulating tumour DNA in patients receiving anticancer immunotherapy

Author: Charlotte Proudhon, Jean-Yves Pierga, Luc Cabel, Marc-Henri Stern, François-Clément Bidard, Nicolas Girard, Olivier Lantz, and Emanuela Romano
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, medicine.medical_treatment, Disease, B7-H1 Antigen, Circulating Tumor DNA, 03 medical and health sciences, 0302 clinical medicine, Cancer immunotherapy, Internal medicine, Neoplasms, Biopsy, medicine, Biomarkers, Tumor, Humans, Pseudoprogression, biology, medicine.diagnostic_test, business.industry, Microsatellite instability, Immunotherapy, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, biology.protein, Antibody, business, Adjuvant
Abstract: Considerable interest surrounds the use of immune-checkpoint inhibitors in patients with solid tumours following the demonstration of the impressive clinical efficacy of anti-programmed cell death protein 1 and anti-programmed cell death 1 ligand 1 antibodies in several tumour types. However, the emergence of unexpected tumour response patterns, such as pseudoprogression or hyperprogression, might complicate the management of patients receiving these agents. Analysis of circulating tumour DNA (ctDNA) has been shown to have prognostic value by enabling the detection of residual proliferating disease in the adjuvant setting and estimation of tumour burden in the metastatic setting, which are key stratification biomarkers for use of immune-checkpoint inhibition (ICI). Furthermore, examinations of ctDNA for genetic predictors of responsiveness to immunotherapy, such as mutations, tumour mutational load, and microsatellite instability provide a noninvasive surrogate for tumour biopsy sampling. Proof-of-concept reports have also demonstrated that quantitative changes in ctDNA levels early in the course of disease are a promising tool for the assessment of responsiveness to ICI that might complement standard imaging approaches. Other applications of this technology are also currently under investigation, such as early detection of resistance to immunotherapy and characterization of mechanisms of resistance. The aim of this Review is to summarize available data on the application of ctDNA in patients receiving immunotherapy and to discuss the most promising future directions.
Published: 2018

28. Publisher Correction: Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors

Author: Vincent Rouilly, Cherie Green, Lluis Quintana-Murci, Julie Hunkapiller, Isabelle Peguillet, Magnus Fontes, Jacob Bergstedt, Alejandra Urrutia, Claire Leloup, Benoit Beitz, Friederike Jönsson, Darragh Duffy, Stéphanie Thomas, François Huetz, Lars Rogge, Cécile Alanio, Matthew L. Albert, Petar Scepanovic, Olivier Lantz, Barbara Piasecka, Yoong Wearn Lim, Jacques Fellay, Hélène Quach, Christian Hammer, Milena Hasan, Etienne Patin, Magge Zepeda, Valentina Libri, and James P. Di Santo
Subjects: 0301 basic medicine, Innate immune system, Immunology, Computational biology, Biology, Natural variation, InformationSystems_GENERAL, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Correct name, Immunology and Allergy
Abstract: In the version of this article initially published, the name of one author was incorrect (James P. Santo). The correct name is James P. Di Santo. The error has been corrected in the HTML and PDF versions of the article.
Published: 2018

29. Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors

Author: Sergio Roman-Roman, Marc-Henri Stern, Pascale Mariani, Stéphane Dayot, François-Clément Bidard, Alexandre Houy, Marc Putterman, Sophie Piperno-Neumann, Vincent Servois, Lenha Mobuchon, Tatiana Popova, Alice Fiévet, Virginie Raynal, Manuel Rodrigues, Raymond L. Barnhill, Aurore Rampanou, Nathalie Cassoux, Olivier Lantz, Sophie Gardrat, Aurore Mouton, Michèle Galut, and Sarah Tick
Subjects: 0301 basic medicine, Uveal Neoplasms, Somatic cell, Science, Programmed Cell Death 1 Receptor, General Physics and Astronomy, Loss of Heterozygosity, Disease, Antibodies, Monoclonal, Humanized, General Biochemistry, Genetics and Molecular Biology, Germline, Article, Eye Enucleation, MBD4, Loss of heterozygosity, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, Atlases as Topic, medicine, Humans, Point Mutation, lcsh:Science, Melanoma, Germ-Line Mutation, Aged, Multidisciplinary, Endodeoxyribonucleases, business.industry, Genome, Human, General Chemistry, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, CpG site, 030220 oncology & carcinogenesis, Lymphatic Metastasis, Cancer research, lcsh:Q, CpG Islands, Female, business
Abstract: Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors., Hypermutated tumors respond more favorably to checkpoint inhibitor-based immune therapy. Here, the authors describe a new hypermutated phenotype due to germline mutations and subsequent somatic loss of heterozygosity of MBD4, and a dramatic response to the PD-1 inhibitor pembrolizumab in a patient with a MBD4-inactivated hypermutated uveal melanoma.
Published: 2018

30. Complementarity and redundancy of IL-22-producing innate lymphoid cells

Author: Sabrina Carpentier, Sebastian Carotta, Tracy L Putoczki, Nicholas D. Huntington, Lisa A. Mielke, Stanislas Mondot, Yann M. Kerdiles, Olivier Lantz, Mohamed Lamkanfi, Eric Vivier, Wei Shi, Gordon K. Smyth, Elisabeth Wieduwild, Cyril Seillet, Aurore Fenis, Lucille C. Rankin, Gabrielle T. Belz, Tim Soos, Jean-Christophe Renauld, Sophie Ugolini, Christopher Arendt, Dieter Demon, Mathilde J. H. Girard-Madoux, Anthony T. Papenfuss, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Health and Medical Research Council of Australia, Dora Lush Postgraduate Research Scholarship, Australian Research Council, Victorian State Government Operational Infrastructure Support, Australian Government National Health and Medical Research Council Independent Research Institutes Infrustructure Support, European Research Council (THINK Advanced Grant), Ligue Nationale contre le Cancer (Equipe Labellisee), INSERM, CNRS, Aix-Marseille University, Institut Universitaire de France, European Project: 268537,EC:FP7:ERC,ERC-2010-AdG_20100317,THINK(2011), UCL - SSS/DDUV - Institut de Duve, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: Male, 0301 basic medicine, viruses, ILC3, Transcriptome, Interleukin 22, Mice, 0302 clinical medicine, Cluster Analysis, Homeostasis, Immunology and Allergy, Lymphocytes, Cecal homeostasis, Mice, Knockout, Innate lymphoid cell, Enterobacteriaceae Infections, virus diseases, Cell biology, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, Signal Transduction, Cells, T cell, Immunology, Mice, Transgenic, Inflammation, Biology, digestive system, Article, 03 medical and health sciences, Immune system, Immunity, medicine, Animals, Natural Cytotoxicity Triggering Receptor 1, Gene Expression Profiling, Interleukins, Immunity, Innate, Lymphocyte Subsets, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, Citrobacter rodentium, Myeloid Cell Leukemia Sequence 1 Protein, T-Box Domain Proteins, 030215 immunology
Abstract: International audience; Intestinal T cells and group 3 innate lymphoid cells (ILC3 cells) control the composition of the microbiota and gut immune responses. Within the gut, ILC3 subsets coexist that either express or lack the natural cytoxicity receptor (NCR) NKp46. We identified here the transcriptional signature associated with the transcription factor T-bet-dependent differentiation of NCR- ILC3 cells into NCR+ ILC3 cells. Contrary to the prevailing view, we found by conditional deletion of the key ILC3 genes Stat3, 1122, Tbx21 and Mcl1 that NCR+ ILC3 cells were redundant for the control of mouse colonic infection with Citrobacter rodentium in the presence of T cells. However, NCR+ ILC3 cells were essential for cecal homeostasis. Our data show that interplay between intestinal ILC3 cells and adaptive lymphocytes results in robust complementary failsafe mechanisms that ensure gut homeostasis.
Published: 2015

31. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations

Author: Jean-Pierre de Villartay, Luigi D. Notarangelo, Caroline Deswarte, Danielle T. Avery, Rubén Martínez-Barricarte, Masao Kobayashi, Claire Soudais, Dina Averbuch, Fabienne Jabot-Hanin, Egídio Torrado, Chizuru Okada, Stuart G. Tangye, Yuval Itan, Despina Moshous, Bertrand Boisson, Cindy S. Ma, Anne Puel, M. Lagos, Capucine Picard, Mohammed Alzahrani, Jamie Rossjohn, Rabih Halwani, Elissa K. Deenick, Jeffrey J. Fountain, Jamal Shamma, Jacinta Bustamante, Mélanie Migaud, Natalie Wong, Dan Engelhard, Daniela Latorre, Aziz Belkadi, Sylvain Breton, Sylvain Latour, Federico Mele, Janet Markle, Marcela Gonzalez, Hiyam Marzouqa, Sophie Hambleton, Stéphanie Boisson-Dupuis, Laurent Abel, James McCluskey, Federica Sallusto, Alessandro Sette, Peter D. Arkwright, Saleh Al-Muhsen, Olivier Lantz, Jean-Laurent Casanova, Lauren A. Henderson, Andrea M. Cooper, Cecilia S. Lindestam Arlehamn, and Satoshi Okada
Subjects: 0303 health sciences, Multidisciplinary, biology, T cell, Gene rearrangement, Mucocutaneous Candidiasis, medicine.disease, biology.organism_classification, Chronic Candidiasis, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, RAR-related orphan receptor gamma, Immunity, Immunology, medicine, Chronic mucocutaneous candidiasis, Candida albicans, 030304 developmental biology, 030215 immunology
Abstract: A surprising immune twist for RORC The immune system needs its full array of soldiers—including cells and the molecules they secrete—to optimally protect the host. When this isn't the case, minor infections can become chronic or even deadly. Markle et al. report the discovery of seven individuals carrying loss-of-function mutations in RORC, which encodes the transcription factors RORγ and RORγT. These individuals lacked immune cells that produce the cytokine interleukin-17, causing them to suffer from chronic candidiasis. RORC-deficient individuals also exhibited impaired immunity to mycobacterium, probably due to reduced production of the cytokine interferon-γ, a molecule not known to require RORC for its induction. Science , this issue p. 606
Published: 2015

32. Ontogeny of human mucosal-associated invariant T cells and related T cell subsets

Author: Jean-Sébastien Diana, Michel Peuchmaur, Jean-Hugues Dalle, Valérie Biran, Saba Azarnoush, Marie Tourret, Véronique Houdouin, Liana Ghazarian, Thomas Schmitz, Ghada Ben Youssef, Yvonne K. Mburu, Marion Lambert, Olivier Lantz, Sophie Caillat-Zucman, Marion Salou, Anne-Laure Virlouvet, Stanislas Mondot, Ben Youssef, Ghada, Tourret, Marie, Salou, Marion, Ghazarian, Liana, Dalle, Jean-Hugues, Lantz, Olivier, Biran, Valérie, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Curie [Paris], Département de Biopathologie, Hôpital Saint-Louis, Agence Nationale de la Recherche (ANR), Direction Generale de l'Offre de Soins (DGOS) PRTS 14-CE15-0005, Institut National du Cancer (INCa) 2012-059, Agence de Biomedecine, Cent pour Sang la vie, IRG HET, Fondation pour la Recherche Medicale (FRM) ING20150532367, Agence Nationale de la Recherche grants from the 'Investissements d'Avenir' program ANR-10-EQPX-03 ANR-10-INBS-09-08, Canceropole Ile-de-France, and SiRIC-Curie program INCa-DGOS-4654
Subjects: 0301 basic medicine, Adult, Male, Ontogeny, T cell, [SDV]Life Sciences [q-bio], Immunology, Receptors, Antigen, T-Cell, Mucosal associated invariant T cell, Biology, Infections, Mucosal-Associated Invariant T Cells, Article, Minor Histocompatibility Antigens, 03 medical and health sciences, 0302 clinical medicine, Antigen, Pregnancy, T-Lymphocyte Subsets, medicine, Immunology and Allergy, Humans, Cord blood transplantation, Research Articles, Antigens, Bacterial, Histocompatibility Antigens Class I, MAIT Cells, Infant, Newborn, Cell Differentiation, Fetal Blood, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Cord blood, Female, 030215 immunology, NK Cell Lectin-Like Receptor Subfamily B
Abstract: There are very few human MAIT cells in cord blood. Ben Youssef et al. show that they slowly expand during childhood and point to a critical role of the TCRαβ repertoire in determining their unique ability to recognize MR1-restricted microbial antigens., Mucosal-associated invariant T (MAIT) cells are semi-invariant Vα7.2+ CD161highCD4− T cells that recognize microbial riboflavin precursor derivatives such as 5-OP-RU presented by MR1. Human MAIT cells are abundant in adult blood, but there are very few in cord blood. We longitudinally studied Vα7.2+ CD161high T cell and related subset levels in infancy and after cord blood transplantation. We show that Vα7.2+ and Vα7.2− CD161high T cells are generated early during gestation and likely share a common prenatal developmental program. Among cord blood Vα7.2+ CD161high T cells, the minority recognizing MR1:5-OP-RU display a TRAV/TRBV repertoire very similar to adult MAIT cells. Within a few weeks of life, only the MR1:5-OP-RU reactive Vα7.2+ CD161high T cells acquire a memory phenotype. Only these cells expand to form the adult MAIT pool, diluting out other Vα7.2+ CD161high and Vα7.2− CD161high populations, in a process requiring at least 6 years to reach adult levels. Thus, the high clonal size of adult MAIT cells is antigen-driven and likely due to the fine specificity of the TCRαβ chains recognizing MR1-restricted microbial antigens.
Published: 2017

33. Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study

Author: Charlotte Proudhon, Maud Milder, E. Romano, Catherine Daniel, Ivan Bièche, Alain Livartowski, Jean-Yves Pierga, Vincent Servois, Sophie Piperno-Neumann, François-Clément Bidard, Sylvain Baulande, Bruno Buecher, Luc Cabel, Francesca Riva, Aurore Rampanou, Olivier Lantz, and Virginie Bernard
Subjects: 0301 basic medicine, Male, Colorectal cancer, medicine.medical_treatment, Pilot Projects, Pembrolizumab, Polymerase Chain Reaction, B7-H1 Antigen, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, medicine, Humans, Progression-free survival, Prospective Studies, Aged, Monitoring, Physiologic, Aged, 80 and over, business.industry, Melanoma, Hematology, Immunotherapy, DNA, Neoplasm, Middle Aged, medicine.disease, Prognosis, Survival Analysis, Immune checkpoint, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, Biomarker (medicine), Female, Nivolumab, business
Abstract: Recent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB.This prospective pilot study was conducted in patients with nonsmall cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels were assessed at baseline and after 8 weeks (w8) by bidirectional pyrophosphorolysis-activated polymerization, droplet digital PCR or next-generation sequencing depending on the mutation type. Radiological evaluation of efficacy of treatment was carried out by using immune-related response criteria.ctDNA was detected at baseline in 10 out of 15 patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed between synchronous changes in ctDNA levels and tumor size. Patients in whom ctDNA levels became undetectable at w8 presented a marked and lasting response to therapy. ctDNA detection at w8 was also a significant prognostic factor in terms of progression-free survival (hazard ratio = 10.2; 95% confidence interval 2.5-41, P 0.001) and overall survival (hazard ratio = 15; 95% confidence interval 2.5-94.9, P = 0.004).This proof-of-principle study is the first to demonstrate that quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.
Published: 2017

34. Multiple Hotspot Mutations Scanning by Single Droplet Digital PCR

Author: Charles Decraene, Olivier Lantz, Charlotte Proudhon, Audrey Vallée, Samia Melaabi, Adrien Saliou, Maud Milder, Amanda Bortolini Silveira, Alexandre Houy, Marc Michel, Marc-Henri Stern, François-Clément Bidard, Marc Ychou, Jean-Yves Pierga, Marc G. Denis, Anne Vincent-Salomon, Bernardo, Elizabeth, Laboratoire des biomarqueurs tumoraux circulants [Institut Curie, Paris] (SiRIC - Département de recherche translationnelle), Institut Curie [Paris]-Université Paris sciences et lettres (PSL), Compartimentation et dynamique cellulaires (CDC), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Curie [Paris], Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de Biochimie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Nord Laennec [CHU Nantes], Département de Biopathologie [Institut Curie, Paris], Génétique et Biologie du Développement, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité et cancer (U932), Département d'oncologie médicale [CHU Montpellier], Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Biopsy, Clinical Biochemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, Polymerase Chain Reaction, Circulating Tumor DNA, 03 medical and health sciences, Exon, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Limit of Detection, Neoplasms, medicine, Humans, Digital polymerase chain reaction, Liquid biopsy, Lung cancer, Gene, medicine.diagnostic_test, Biochemistry (medical), Liquid Biopsy, medicine.disease, Molecular biology, 3. Good health, ErbB Receptors, 030104 developmental biology, Genes, ras, 030220 oncology & carcinogenesis, Molecular Probes, Mutation, Cancer research, KRAS, Molecular probe
Abstract: BACKGROUND Progress in the liquid biopsy field, combined with the development of droplet digital PCR (ddPCR), has enabled noninvasive monitoring of mutations with high detection accuracy. However, current assays detect a restricted number of mutations per reaction. ddPCR is a recognized method for detecting alterations previously characterized in tumor tissues, but its use as a discovery tool when the mutation is unknown a priori remains limited. METHODS We established 2 ddPCR assays detecting all genomic alterations within KRAS exon 2 and EGFR exon 19 mutation hotspots, which are of clinical importance in colorectal and lung cancer, with use of a unique pair of TaqMan® oligoprobes. The KRAS assay scanned for the 7 most common mutations in codons 12/13 but also all other mutations found in that region. The EGFR assay screened for all in-frame deletions of exon 19, which are frequent EGFR-activating events. RESULTS The KRAS and EGFR assays were highly specific and both reached a limit of detection of CONCLUSIONS This method presents the advantage of detecting a higher number of mutations with single-reaction ddPCRs while consuming a minimum of patient sample. This is particularly useful in the context of liquid biopsy because the amount of circulating tumor DNA is often low. This method should be useful as a discovery tool when the tumor tissue is unavailable or to monitor disease during therapy.
Published: 2017

35. MAIT cells: an historical and evolutionary perspective

Author: Olivier Lantz and François Legoux
Subjects: 0301 basic medicine, Immunology, Computational biology, Biology, History, 21st Century, Mucosal-Associated Invariant T Cells, 03 medical and health sciences, 0302 clinical medicine, Antigen, Phylogenetics, Allergy and Immunology, MHC class I, Immunology and Allergy, Animals, Humans, Phylogeny, Phylogenetic tree, Repertoire, T-cell receptor, Cell Biology, History, 20th Century, Natural killer T cell, Phenotype, Biological Evolution, 030104 developmental biology, biology.protein, 030215 immunology
Abstract: In humans, MAIT cells represent the most abundant T-cell subset reacting against bacteria. MAIT cells belong to the evolutionarily conserved family of "preset" T cells that includes also NKT cells. Both subsets are selected by double positive thymocytes leading to common features such as PLZF expression. Preset T cells correspond to subsets prepositioned in specific tissue locations with preprogrammed versatile effector functions such as antimicrobial functions and possibly also metabolic control and tissue repair activity. Herein, we recall how several groups studying human samples discovered MAIT cells as T cells expressing either a restricted T-cell receptors (TCR) repertoire or homogeneous and singular phenotypic and functional characteristics. We then highlight the main evolutionary features of this subset and its restricting element, MR1 (MHC-related protein (1) with a striking coevolution of TRAV1 and MR1. We introduce another evolutionarily conserved invariant TCRalpha chain coevolving with another MHC class Ib molecule, called MHX, sharing phylogenetic features with MR1. We finally discuss the relationship between MAIT cells and other subsets reacting to microbial antigens or to compounds presented by MR1 in light of confounding experimental issues.
Published: 2017
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36. Extrathymic induction of Foxp3+regulatory T cells declines with age in a T-cell intrinsic manner

Author: David-Alexandre Gross, Odile Burlen-Defranoux, Héloïse Flament, Bernard Malissen, Mélanie Lalfer, Pascal Chappert, Olivier Lantz, Maxime Carpentier, Antonio Bandeira, Chantal Kuhn, and Jean Davoust
Subjects: Senescence, 0303 health sciences, T cell, Immunology, T-cell receptor, FOXP3, hemic and immune systems, chemical and pharmacologic phenomena, Stimulation, Biology, Immune tolerance, Transplantation, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, medicine, biology.protein, Immunology and Allergy, Antibody, 030304 developmental biology, 030215 immunology
Abstract: Extrathymically induced Foxp3+ regulatory T (Treg) cells contribute to the pool of Treg cells and are implicated in the maintenance of immune tolerance at environmental interfaces. The impact of T-cell senescence on their generation and function is, however, poorly characterized. We report here that steady-state induction of Foxp3 is impaired in aged T cells in vivo. In vitro assays further revealed that this defective generation of Treg cells was independent from the strength of TCR stimulation and arose before T-cell proliferation. Importantly, they also revealed that this impairment of Foxp3 induction is unrelated to known age-related T-cell defects, such as IL-2 secretion impairment, accumulation of activated T-cell populations, or narrowing of the T-cell repertoire. Finally, a loss of extrathymic induction of Foxp3 and tolerance to minor-mismatched skin graft were observed in aged mice treated by nondepleting anti-CD4 antibody. The T-cell intrinsic impairment of Treg-cell generation revealed here highlights age as a key factor to be considered in immune tolerance induction.
Published: 2013

37. Recipient mucosal-associated invariant T cells control GVHD within the colon

Author: Jamie Rossjohn, Motoko Koyama, Nancy Lachner, Kate L. Ormerod, Renee J. Robb, Geoffrey R. Hill, James McCluskey, Steven W. Lane, Lars Kjer-Nielsen, Philip Hugenholtz, Kate H. Gartlan, Rachel D. Kuns, Andrea S. Henden, Antiopi Varelias, Mark D. Bunting, Jeffrey Y. W. Mak, David P. Fairlie, Stuart D. Olver, Leanne Cooper, Andrew D. Clouston, Olivier Lantz, and Jasmin Straube
Subjects: 0301 basic medicine, Colon, medicine.medical_treatment, T cell, Population, Graft vs Host Disease, chemical and pharmacologic phenomena, Mucosal associated invariant T cell, Biology, Mucosal-Associated Invariant T Cells, 03 medical and health sciences, Colonic Diseases, Mice, 0302 clinical medicine, Immunity, MHC class I, medicine, Animals, education, Bone Marrow Transplantation, Mice, Knockout, education.field_of_study, Mice, Inbred BALB C, General Medicine, Allografts, Transplantation, 030104 developmental biology, Cytokine, medicine.anatomical_structure, surgical procedures, operative, Immunology, biology.protein, Th17 Cells, Female, Interleukin 17, 030215 immunology, Research Article
Abstract: Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I-like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A-/- and MR1-/- mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A-dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT.
Published: 2016

38. Restricting nonclassical MHC genes coevolve with TRAV genes used by innate-like T cells in mammals

Author: Luc Jouneau, Marie-Paule Lefranc, Luc Teyton, Stanislas Mondot, Olivier Lantz, Pierre Boudinot, ProdInra, Migration, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Université Paris Saclay (COmUE), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology and Microbial Science, The Scripps Research Institute [La Jolla, San Diego], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Laboratoire d'Immunologie Clinique, Institut Curie [Paris], Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Scripps Research Institute, and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, [SDV]Life Sciences [q-bio], Complementarity determining region, Major histocompatibility complex, Evolution, Molecular, 03 medical and health sciences, Negative selection, 0302 clinical medicine, evolution, Animals, mammals, Gene, Genetics, Multidisciplinary, biology, Histocompatibility Antigens Class I, T-cell receptor, RNA, Natural killer T cell, Complementarity Determining Regions, [SDV] Life Sciences [q-bio], 030104 developmental biology, PNAS Plus, CD1D, Cats, biology.protein, Rabbits, MHC, MAIT, TCR, 030215 immunology
Abstract: International audience; Whereas major histocompatibility class-1 (MH1) proteins present peptides to T cells displaying a large T-cell receptor (TR) repertoire, MH1Like proteins, such as CD1D and MR1, present glycolipids and microbial riboflavin precursor derivatives, respectively, to T cells expressing invariant TR-α (iTRA) chains. The groove of such MH1Like, as well as iTRA chains used by mucosal-associated invariant T (MAIT) and natural killer T (NKT) cells, respectively, may result from a coevolution under particular selection pressures. Herein, we investigated the evolutionary patterns of the iTRA of MAIT and NKT cells and restricting MH1Like proteins: MR1 appeared 170 Mya and is highly conserved across mammals, evolving more slowly than other MH1Like. It has been pseudogenized or independently lost three times in carnivores, the armadillo, and lagomorphs. The corresponding TRAV1 gene also evolved slowly and harbors highly conserved complementarity determining regions 1 and 2. TRAV1 is absent exclusively from species in which MR1 is lacking, suggesting that its loss released the purifying selection on MR1. In the rabbit, which has very few NKT and no MAIT cells, a previously unrecognized iTRA was identified by sequencing leukocyte RNA. This iTRA uses TRAV41, which is highly conserved across several groups of mammals. A rabbit MH1Like gene was found that appeared with mammals and is highly conserved. It was independently lost in a few groups in which MR1 is present, like primates and Muridae, illustrating compensatory emergences of new MH1Like/Invariant T-cell combinations during evolution. Deciphering their role is warranted to search similar effector functions in humans.
Published: 2016

39. MAIT, MR1, microbes and riboflavin: a paradigm for the co-evolution of invariant TCRs and restricting MHCI-like molecules?

Author: Olivier Lantz, Pierre Boudinot, Stanislas Mondot, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Institut Curie, Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Université Paris-Saclay, and Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892))
Subjects: 0301 basic medicine, In silico, T cell, Riboflavin, [SDV]Life Sciences [q-bio], Immunology, Antigen presentation, Receptors, Antigen, T-Cell, MAIT cells, Bacterial genome size, Mucosal associated invariant T cell, Biology, Major histocompatibility complex, Mucosal-Associated Invariant T Cells, Evolution, Molecular, Minor Histocompatibility Antigens, 03 medical and health sciences, 0302 clinical medicine, Antigen, T-Lymphocyte Subsets, Genetics, medicine, Animals, Humans, Antigen Presentation, Antigens, Bacterial, Histocompatibility Antigens Class I, T-cell receptor, Bacterial, MR1, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Biochemistry, biology.protein, Invariant TCR, 030215 immunology
Abstract: MAIT cells express an invariant TCR that recognizes non-peptidic microbial antigens presented by the non-polymorphic MHCI-like molecule, MR1. We briefly describe how the antigens recognized by MAIT cells are generated from an unstable precursor of the riboflavin (Vitamin B2) biosynthesis pathway, as well as the main features of MAIT cells in comparison with other related T cell subsets. In silico analysis of bacterial genomes shows that the riboflavin biosynthesis pathway is highly prevalent in all groups of Prokaryotes with, however, notable exceptions. We discuss the putative functions and the evolution of the MAIT/MR1 couple: it appeared in the ancestors of mammals and is highly conserved across this group, but was independently lost in three orders. We describe the four instances of known invariant TCR and MHC-I-like molecules encountered in Vertebrates. Both T cells bearing semi-invariant TCR and the associated, evolutionarily conserved MHC-I related molecules have been found in mammals or in amphibians, which suggests that other MHC1-like/invariant TCR couples might be present in other classes of Vertebrates to detect generic microbial compounds. This allows us to discuss how the recognition of riboflavin precursor derivatives by the MAIT TCR may be a way to detect invasive microbes in specific organs, and may epitomize other invariant T cell systems across vertebrates.
Published: 2016

40. UM Cure 2020 - A consortium of European experts in uveal melanoma to identify new therapies for patients with metastatic disease

Author: Rob Ruijtenbeek, Maria Caterina Mione, Sophie Piperno-Neumann, M-H Stern, Didier Decaudin, Sergio Roman-Roman, Nathalie Cassoux, B.E. Snaar-Jagalska, H. Hafsi, André Valente, Bettina Ryll, Aart G Jochemsen, Martyna Elas, N. Dhomen, M.J. Jager, Sarah E. Coupland, Helen Kalirai, Raymond L. Barnhill, B. Romanowska Dixon, Olivier Lantz, P.A. van der Velden, A. Prestat, and Richard Marais
Subjects: medicine.medical_specialty, business.industry, Melanoma, General Medicine, Disease, medicine.disease, Dermatology, 03 medical and health sciences, Ophthalmology, 0302 clinical medicine, 030221 ophthalmology & optometry, Medicine, business, 030217 neurology & neurosurgery
Published: 2016
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41. Clinical applications of circulating tumor DNA and circulating tumor cells in pancreatic cancer

Author: Florence Huguet, Charlotte Proudhon, Christophe Louvet, Olivier Lantz, Francesca Riva, Dronov Oi, Jean-Yves Pierga, Dmytro I. Khomenko, François-Clément Bidard, Pascale Mariani, and Marc-Henri Stern
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Epithelial-Mesenchymal Transition, endocrine system diseases, Reviews, Tumor M2-PK, Context (language use), Disease, 03 medical and health sciences, 0302 clinical medicine, Circulating tumor cell, Internal medicine, Pancreatic cancer, Genetics, medicine, Biomarkers, Tumor, Animals, Humans, Epithelial–mesenchymal transition, Liquid biopsy, Neoplasm Metastasis, business.industry, Pancreatic Ducts, General Medicine, DNA, Neoplasm, medicine.disease, Neoplastic Cells, Circulating, Prognosis, Pancreatic Neoplasms, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Molecular Medicine, CA19-9, business, Carcinoma, Pancreatic Ductal
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is the most frequent pancreatic cancer type and is characterized by a dismal prognosis due to late diagnosis, local tumor invasion, frequent distant metastases and poor sensitivity to current therapy. In this context, circulating tumor cells and circulating tumor DNA constitute easily accessible blood-borne tumor biomarkers that may prove their clinical interest for screening, early diagnosis and metastatic risk assessment of PDAC. Moreover these markers represent a tool to assess PDAC mutational landscape. In this review, together with key biological findings, we summarize the clinical results obtained using "liquid biopsies" at the different stages of the disease, for early and metastatic diagnosis as well as monitoring during therapy.
Published: 2015

42. Abstract 1690: NKG2A immune checkpoint blockade potentiates cetuximab induced ADCC in head and neck cancer preclinical model

Author: Romain Remark, Elodie Bonnet, Olivier Lantz, Violette Breso, Caroline Soulas, Eric Vivier, Ana Ines Lalanne, Caroline Hoffman, Pascale Andre, Cécile Bonnafous, Arnaud Dujardin, and Mathieu Blery
Subjects: 0301 basic medicine, Cancer Research, Cetuximab, business.industry, T cell, CD137, Cancer, medicine.disease, Immune checkpoint, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, medicine, Cancer research, Monalizumab, business, Lymph node, CD8, medicine.drug
Abstract: Monalizumab (IPH2201) is a first-in-class humanized IgG4 targeting NKG2A (Natural Killer Group 2A), which is expressed as a heterodimer with CD94 at the surface of subsets of NK (Natural Killer) cells, γδ T cells and tumor infiltrating CD8+ T cells. This inhibitory receptor binds to HLA-E (Human Leukocytes Antigen-E) molecules that are frequently up-regulated on human cancer cells, preventing from killing by NKG2A+ immune cells. HLA-E is expressed on most of the patients with Head and Neck Squamous Cell Cancer (HNSCC). Monalizumab blocks the binding of CD94/NKG2A to HLA-E, reducing inhibitory signaling thereby unleashing NK and T cell responses. High expression of EGFR occurs in most epithelial malignancies and particularly in HNSCC and is associated with poor prognosis. The anti-EGFR monoclonal antibody cetuximab (Ctx) is thought to act through blocking oncogenic signaling and by inducing Fcγ receptor-mediated antibody dependent cell cytotoxicity (ADCC) which involves human NK cells. We investigated ex vivo and in vitro the rationale of combining monalizumab with Ctx in the treatment of oral cancers. We first analyzed formalin-fixed paraffin-embedded samples of HNSCC patients by immunohistochemistry (n=65). We confirmed that HLA-E was expressed on carcinoma cells in all patients. We also observed that most of the tumors were highly infiltrated by CD8+ T cells both in the tumor beds and in the stroma and that the majority of tumors were also infiltrated by NKp46+ NK cells in higher numbers in the non-metastatic tumors. Interestingly, HNSCC was found as being one of the tumor types with the highest NKp46+ cell density as compared with renal cell carcinoma, non-small cell lung cancer, colorectal cancer or pancreatic tumors. Moreover CD94+ lymphocytes were detected in the stroma and tumor beds in close contact to tumor cells in about half of the patients. Using multicolor flow cytometry, NK cells and CD8+ T cells from tumor and non-involved adjacent tissues, metastatic lymph nodes and peripheral blood from patients relapsing post-chemotherapy were characterized for expression of activating and inhibitory receptors. Interestingly, NKG2A expression was higher on tumor infiltrating NK cells (CD56dim or CD56bright) and CD8+ T cell compared to the one observed in non-involved adjacent tissue, metastatic lymph node or blood. In vitro, monalizumab increased CD107 mobilization and CD137 upregulation on NKG2A+ NK cells in response to HNSCC cell lines with endogenous HLA-E expression and enhanced Ctx-mediated ADCC in a dose dependent manner. Altogether, these data support the rationale for investigating monalizumab in HNSCC patients and in combination with cetuximab in clinical trials (NCT02643550). Citation Format: Caroline Soulas, Ana Lalanne, Cécile Bonnafous, Caroline Hoffman, Elodie Bonnet, Arnaud Dujardin, Violette Breso, Mathieu Bléry, Olivier Lantz, Romain Remark, Eric Vivier, Pascale Andre. NKG2A immune checkpoint blockade potentiates cetuximab induced ADCC in head and neck cancer preclinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1690.
Published: 2018

43. A first-in-human study of monoclonal antibody GM102 in patients with anti-Mullerian-hormone-receptor II (AMHRII) positive gynecological cancers

Author: Andrea Varga, Francesco Ricci, Philippe Aftimos, Jean-Pierre Delord, Agnès Coste, Guillaume Bataillon, Grégory Noël, Carlos Gomez-Roca, Isabelle Tabah-Fisch, Jean-François Prost, Alexandra Leary, Anne Vincent Salomon, Lydie Cassard, Nathalie Van Acker, Christophe Le Tourneau, Bérengère Jean, Christiane Jungels, Olivier Lantz, Ahmad Awada, and Isabelle Ray-Coquard
Subjects: 0301 basic medicine, endocrine system, Cancer Research, endocrine system diseases, urogenital system, medicine.drug_class, Mullerian Ducts, business.industry, Embryo, First in human, Monoclonal antibody, female genital diseases and pregnancy complications, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, Cell surface receptor, 030220 oncology & carcinogenesis, Anti-Müllerian hormone receptor, medicine, Cancer research, In patient, business
Abstract: 5542Background: AMH and its membrane receptor AMHRII induce regression of Mullerian ducts in the male embryo. AMHRII is constitutively expressed in ovarian granulosa tumors (GCT) and re-expressed i...
Published: 2018

44. Mucosal-associated invariant T cell–rich congenic mouse strain allows functional evaluation

Author: Lionel Le Bourhis, Olivier Lantz, Yue Cui, Katarzyna Franciszkiewicz, Yvonne K. Mburu, Sylvie Rabot, Alexandra Kachaner, Emmanuel Martin, Claire Soudais, Stanislas Mondot, Virginie Premel, Livine Duban, Jean Jaubert, Molly A. Ingersoll, Jean-Pierre de Villartay, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Génétique Fonctionnelle de la Souris, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biopathologie, Institut Curie [Paris], This work was supported by grants from INSERM, Agence Nationale de la Recherche (ANR), DIM Ile de France, Association pour la Recherche sur la Sclérose En Plaques (ARSEP), Institut Mérieux, and Institut Curie. Y.K. Mburu is a recipient of the Lloyd J. Old Memorial Award and is supported by an Irvington Institute postdoctoral fellowship from the Cancer Research Institute., Vougny, Marie-Christine, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Curie
Subjects: MESH: Minor Histocompatibility Antigens, MESH: Nuclear Receptor Subfamily 1, Group F, Member 3, Receptors, Antigen, T-Cell, alpha-beta, MESH: Chemotaxis, Leukocyte, MESH: Urinary Tract Infections, Lymphocyte Activation, MESH: Mice, Knockout, MESH: Histocompatibility Antigens Class I, MESH: Promyelocytic Leukemia Zinc Finger Protein, Mice, 0302 clinical medicine, Promyelocytic Leukemia Zinc Finger Protein, MESH: Animals, Mice, Knockout, 0303 health sciences, education.field_of_study, Lymphokines, MESH: Receptors, Antigen, T-Cell, alpha-beta, Microbiota, MESH: Polymorphism, Single Nucleotide, General Medicine, Nuclear Receptor Subfamily 1, Group F, Member 3, Natural killer T cell, MESH: Crosses, Genetic, Chemotaxis, Leukocyte, medicine.anatomical_structure, Phenotype, Radiation Chimera, Urinary Tract Infections, MESH: Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor, MESH: Immunologic Memory, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Kruppel-Like Transcription Factors, Research Article, MESH: Lymphocyte Count, [SDV.IMM] Life Sciences [q-bio]/Immunology, Lymphoid Tissue, MESH: Radiation Chimera, MESH: Mice, Transgenic, T cell, Population, Congenic, Kruppel-Like Transcription Factors, Mice, Transgenic, Mucosal associated invariant T cell, Biology, MESH: Phenotype, Polymorphism, Single Nucleotide, Minor Histocompatibility Antigens, 03 medical and health sciences, Mice, Congenic, MESH: Mice, Congenic, MESH: Mice, Inbred C57BL, MESH: Germ-Free Life, medicine, Animals, Germ-Free Life, Humans, MESH: Microbiota, Lymphocyte Count, Receptors, Cytokine, education, MESH: Lymphocyte Activation, MESH: Mice, Crosses, Genetic, 030304 developmental biology, MESH: Humans, MESH: Lymphokines, T-cell receptor, Histocompatibility Antigens Class I, Laboratory mouse, Gene rearrangement, Molecular biology, MESH: Receptors, Cytokine, Mice, Inbred C57BL, Disease Models, Animal, MESH: Natural Killer T-Cells, MESH: Lymphoid Tissue, Natural Killer T-Cells, MESH: Disease Models, Animal, Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor, Immunologic Memory, MESH: Female, 030215 immunology
Abstract: Mucosal-associated invariant T cells (MAITs) have potent antimicrobial activity and are abundant in humans (5%-10% in blood). Despite strong evolutionary conservation of the invariant TCR-alpha chain and restricting molecule MR1, this population is rare in laboratory mouse strains (approximate to 0.1% in lymphoid organs), and lack of an appropriate mouse model has hampered the study of MAIT biology. Herein, we show that MAITs are 20 times more frequent in clean wild-derived inbred CAST/EiJ mice than in C57BL/6J mice. Increased MAIT frequency was linked to one CAST genetic trait that mapped to the TCR-alpha locus and led to higher usage of the distal V alpha segments, including V alpha 19. We generated a MAIT(hl) congenic strain that was then crossed to a transgenic Rorcgt-GFP reporter strain. Using this tool, we characterized polyclonal mouse MAITs as memory (CD44(+)) CD4(-)CD8(lo/neg) T cells with tissue-homing properties (CCR6*CCR7(-)). Similar to human MAITs, mouse MAITs expressed the cytokine receptors IL-7R, IL-18R alpha, and IL-12R beta and the transcription factors promyelocytic leukemia zinc finger (PLZF) and RAR-related orphan receptory gamma (R0R gamma t). Mouse MAITs produced Th1/2/17 cytokines upon TCR stimulation and recognized a bacterial compound in an MR1-dependent manner. During experimental urinary tract infection, MAITs migrated to the bladder and decreased bacterial load. Our study demonstrates that the MAIT(hi) congenic strain allows phenotypic and functional characterization of naturally occurring mouse MAITs in health and disease.
Published: 2015

45. In Vitro and In Vivo Analysis of the Gram-Negative Bacteria-Derived Riboflavin Precursor Derivatives Activating Mouse MAIT Cells

Author: Frédéric Schmidt, Claire Soudais, Mireille Hervé, Stéphanie Bessoles, Didier Blanot, Lionel Le Bourhis, Fatoumata Samassa, Olivier Lantz, Manal Sarkis, Dominique Mengin-Lecreulx, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Enveloppes Bactériennes et Antibiotiques, Département Microbiologie ( Dpt Microbio ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Département de Chimie, Institut Curie, Unité Mixte de Recherche 176, Institut Curie, Enveloppes Bactériennes et Antibiotiques ( ENVBAC ), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Département Microbiologie (Dpt Microbio), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Enveloppes Bactériennes et Antibiotiques (ENVBAC), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Gram-negative bacteria, Riboflavin, [SDV]Life Sciences [q-bio], Immunology, Cell, Mice, Transgenic, In Vitro Techniques, Ligands, Lymphocyte Activation, medicine.disease_cause, Minor Histocompatibility Antigens, Mice, 03 medical and health sciences, 0302 clinical medicine, In vivo, Escherichia coli, medicine, Animals, [CHIM]Chemical Sciences, Immunology and Allergy, Escherichia coli Infections, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Mucous Membrane, biology, [ SDV ] Life Sciences [q-bio], Histocompatibility Antigens Class I, Flow Cytometry, biology.organism_classification, In vitro, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Biochemistry, Polyclonal antibodies, biology.protein, Natural Killer T-Cells, Cell activation, Bacteria, 030215 immunology
Abstract: Mucosal-associated invariant T (MAIT) cells recognize microbial compounds presented by the MHC-related 1 (MR1) protein. Although riboflavin precursor derivatives from Gram-positive bacteria have been characterized, some level of ligand heterogeneity has been suggested through the analysis of the MAIT cell TCR repertoire in humans and differential reactivity of human MAIT cell clones according to the bacteria. In this study, using Gram-negative bacteria mutated for the riboflavin biosynthetic pathway, we show a strict correlation between the ability to synthesize the 5-amino-ribityl-uracil riboflavin precursor and to activate polyclonal and quasi-monoclonal mouse MAIT cells. To our knowledge, we show for the first time that the semipurified bacterial fraction and the synthetic ligand activate murine MAIT cells in vitro and in vivo. We describe new MR1 ligands that do not activate MAIT cells but compete with bacterial and synthetic compounds activating MAIT cells, providing the capacity to modulate MAIT cell activation. Through competition experiments, we show that the most active synthetic MAIT cell ligand displays the same functional avidity for MR1 as does the microbial compound. Altogether, these results show that most, if not all, MAIT cell ligands found in Escherichia coli are related to the riboflavin biosynthetic pathway and display very limited heterogeneity.
Published: 2015

46. Guidelines for the use of flow cytometry and cell sorting in immunological studies

Author: Guadalupe Herrera, Jens Geginat, Daryl Grummitt, Vincenzo Barnaba, Joanne Lannigan, Beate Rückert, Elisabetta Traggiai, Christian Münz, Susanne Melzer, Ari Waisman, Pratip K. Chattopadhyay, Jonas Hahn, T. Vincent Shankey, S Schmid, Julia Tornack, David W. Hedley, Paolo Dellabona, Jürgen Wienands, Ana Cumano, Ester B. M. Remmerswaal, Christopher A. Hunter, Van Duc Dang, Anis Larbi, Timothy P. Bushnell, Mor Gross, Wenjun Ouyang, Vera S. Donnenberg, Lilly Lopez, Holden T. Maecker, Jenny Mjösberg, Christina Stehle, Yanling Liu, Alan M. Stall, Anja E. Hauser, Yousuke Takahama, Mark C. Dessing, Gergely Toldi, Klaus Warnatz, Raghav Palankar, Sussan Nourshargh, Enrico Lugli, Bimba F. Hoyer, Pleun Hombrink, Bartek Rajwa, Sarah Warth, Isabel Panse, Rachael C. Walker, Silvia Piconese, Andrew Filby, Pärt Peterson, Kilian Schober, Silvia Della Bella, Leonie Wegener, Merle Stein, Anne Cooke, Alessandro Moretta, Deborah Kienhöfer, Andrea Cossarizza, Hyun-Dong Chang, Konrad von Volkmann, Jessica P. Houston, Mübeccel Akdis, Andreas Grützkau, Tristan Holland, Jakob Zimmermann, Jonni S. Moore, Dirk Mielenz, Iain B. McInnes, Bo Huang, Paulo Vieira, Thomas Kroneis, Tobit Steinmetz, Kerstin Juelke, Sharon Sanderson, James V. Watson, Srijit Khan, Sally A. Quataert, Winfried F. Pickl, Annika Wiedemann, Sara De Biasi, Andreas Radbruch, James B. Wing, Susann Müller, Ton N. Schumacher, Katy Rezvani, Gloria Martrus, Alexander Scheffold, Toralf Kaiser, Carlo Pucillo, Lara Gibellini, Anna Rubartelli, Qingyu Cheng, Luca Battistini, David Mirrer, David W. Galbraith, Giovanna Borsellino, Ryan R. Brinkman, Tim R. Mosmann, Laura G. Rico, Anita Dreher, Désirée Kunkel, Francesco Annunziato, Pia Kvistborg, Andrea Gori, Chiara Romagnani, Anat Shemer, Toshinori Nakayama, Francisco Sala-de-Oyanguren, Attila Tárnok, Alfonso Blanco, Anna Iannone, Giuseppe Matarese, Thomas Dörner, Virginia Litwin, Michael Lohoff, Petra Bacher, Jordi Petriz, Lorenzo Moretta, Götz R. A. Ehrhardt, Qianjun Zhang, Andrea Cavani, Barry Moran, Christian Maueröder, Immanuel Andrä, Dirk H. Busch, Joe Trotter, Timothy R D J Radstake, Stipan Jonjić, Fritz Melchers, Hans-Martin Jäck, Beatriz Jávega, Gerald Willimsky, Martin Büscher, Henrik E. Mei, Christine S. Falk, Zhigang Tian, Martin Herrmann, Alice Yue, Steffen Jung, Bart Everts, Frank A. Schildberg, John Bellamy Foster, Giovanna Lombardi, Milena Nasi, John P. Nolan, Todd A. Fehniger, Francesco Dieli, Steffen Schmitt, Andreas Dolf, A. Graham Pockley, Claudia Berek, Josef Spidlen, Megan K. Levings, Werner Müller, Baerbel Keller, René A. W. van Lier, Daisy Philips, Susanne Ziegler, Christian Kurts, Malgorzata J. Podolska, Jürgen Ruland, David Voehringer, Kenneth M. Murphy, Marlous van der Braber, Maria Dolores García-Godoy, Sabine Baumgart, Yi Zhao, Antonio Cosma, Falk Hiepe, Charlotte Esser, Pablo Engel, Marcello Veldhoen, Irmgard Förster, Amy E. Lovett-Racke, Günnur Deniz, Burkhard Ludewig, Esther Schimisky, Cristiano Scottà, Marcello Pinti, Jonathan Rebhahn, Regina Stark, Mario Clerici, Liping Yu, Shimon Sakaguchi, Derek Davies, Anna Katharina Simon, Lorenzo Cosmi, Gabriele Multhoff, Kamran Ghoreschi, Quirin Hammer, Henning Ulrich, J. Paul Robinson, Yvonne Samstag, Olivier Lantz, Hannes Stockinger, Xuetao Cao, Simon Fillatreau, David L. Haviland, Natalio Garbi, C. Neudörfl, Kingston H. G. Mills, Salvador Vento-Asturias, Christian Peth, Philip E. Boulais, Diether J. Recktenwald, Burkhard Becher, Tomas Kalina, Michael D. Leipold, Christoph Goettlinger, Gemma A. Foulds, Jane L. Grogan, Axel R. Schulz, James P. Di Santo, Matthias Schiemann, Michael D. Ward, Britta Engelhardt, Birgit Sawitzki, Annette Oxenius, Carl S. Goodyear, Salomé LeibundGut-Landmann, Wolfgang Beisker, Sue Chow, Carsten Watzl, Marie Follo, Erik Lubberts, Peter Wurst, Thomas Schüler, Andreas Diefenbach, Wolfgang Bauer, Hans-Dieter Volk, Luis E. Muñoz, Elmar Endl, Genny Del Zotto, José-Enrique O'Connor, Mairi McGrath, Paul S. Frenette, Dipartimento di Scienze Biomediche, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Cell Biology, Klinik für Dermatologie, Venerologie und Allergologie, Department of Internal Medicine, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-DENOTHE Center, Neuroimmunology Unit, Santa Lucia Foundation (IRCCS), Inorganic Chemistry II, Universität Bayreuth, Caprotec Bioanalytics GmbH, International Occultation Timing Association European Section (IOTA ES), International Occultation Timing Association European Section, Institut der Leibniz-Gemeinschaft, Berlin, Fondazione Santa Lucia (IRCCS), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, Department of Immunology, Chinese Academy of Medical Sciences, Fondazione Don Carlo Gnocchi, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Immunology Unit, Dept. of Oncology, DIBIT San Raffaele Scientific Institute, Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris], Charité Hospital, Humboldt-Universität zu Berlin, Universitat de Barcelona (UB), Rheumatologie, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Department of Histology and Embryology, University of Rijeka, Weizmann Institute of Science [Rehovot, Israël], Régulation des Infections Rétrovirales, Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Institute of Virology [Zürich], College of Food Science and Technology [Shangai], Shanghai Ocean University, Institute for Medical Microbiology and Hygiene, University of Marburg, Centre for Transplantation, King's College London (MRC), Guy's Hospital [London], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Heinrich Pette Institute [Hamburg], Institute of Translational Medicine, Department of Medicine Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Lipid Laboratory, Università di Genova, Dipartimento di Medicina Sperimentale, Department of Environmental Microbiology, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Experimental Immunology, Helmholtz Centre for Infection Research (HZI), Viral Immunobiology, Universität Zürich [Zürich] = University of Zurich (UZH)-Institute of Experimental Immunology [Zurich], Department of Radiation Oncology [Munich], Ludwig-Maximilians-Universität München (LMU), Department of Mathematics and Statistics, American University, William Harvey Research Institute, Barts and the London Medical School, Cytometry Laboratories and School of Veterinary Medicine, Purdue University [West Lafayette], Osaka University [Osaka], FACS and Array Core Facility, Johannes Gutenberg - Universität Mainz (JGU), Institute for Cognitive Science, University of Osnabrueck, Department of Molecular Immunology, Medizinische Universität Wien = Medical University of Vienna, Universität Leipzig [Leipzig], Institute of Immunology, School of Life Sciences-University of Science & Technology of China [Suzhou], Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Immunology, Processus de Transfert et d'Echanges dans l'Environnement - EA 3819 (PROTEE), Université de Toulon (UTLN), Heinrich-Pette-Institut, Leibniz Institute for Experimental Virology, Enrico Lugli and Pratip K. Chattopadhyay were supported by grants from the Fondazione Cariplo (Grant Ricerca Biomedica 2012/0683), the Italian Ministry of Health (Bando Giovani Ricercatori GR-2011-02347324) and the European Union Marie Curie Career Integration Grant 322093 (all to E.L.). E.L. and P.K.C. are International Society for the Advancement of Cytometry (ISAC) Marylou Ingram scholars. Alice Yue and Ryan R. Brinkman were funded by Genome BC and NSERC. Klaus Warnatz received funding from the German Federal Ministry of Education and Research (BMBF 01EO1303) and the Deutsche Forschungsgemeinschaft (DECIDE, DFG WA 1597/4-1 and the TRR130). The Jung laboratory is supported by funds of the ERC and ISF. Henrik Mei is a 2017-2021 ISAC scholar. Antonio Cosma is supported by the French government program: 'Investissement d'avenir: Equipements d'Excellence' (EQUIPEX)-2010 FlowCyTech, Grant number: ANR-10-EQPX-02-01. Henrik Mei is supported by the Deutsche Forschungsgemeinschaft (DFG, grants Me3644/5-1 and TRR130/TP24)., Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Università degli Studi di Firenze = University of Florence (UniFI)-DENOTHE Center, Institut Pasteur [Paris] (IP), Humboldt University Of Berlin, Universität Bonn = University of Bonn, Università degli studi di Genova = University of Genoa (UniGe), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Universität Leipzig, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Obstetrics & Gynecology, Rheumatology, Pediatrics, Landsteiner Laboratory, Other departments, AII - Inflammatory diseases, Università di Modena e Reggio Emilia, DENOTHE Center-University of Florence, Santa Lucia Foundation ( IRCCS ), International Occultation Timing Association European Section ( IOTA ES ), Fondazione Santa Lucia ( IRCCS ), BC Cancer Agency ( BCCRC ) -British Columbia Cancer Agency Research Centre, Fondazione don Carlo Gnocchi, Fondazione IRCCS, Immunologie des Maladies Virales et Autoimmunes ( IMVA - U1184 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Département d'Immunologie, Humboldt Universität zu Berlin, Universitat de Barcelona ( UB ), Charité, Weizmann Institute of Science, Université de Bonn, Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Singapore Immunology Network ( SIgN ), Agency for Science Technology and Research, College of Food Science and Technology, Centre for Transplantation, King's College London ( MRC ), Erasmus MC University Medical Center, Helmholtz Centre for Environmental Research ( UFZ ), Helmholtz Centre for Infection Research ( HZI ), University of Zürich [Zürich] ( UZH ) -Institute of Experimental Immunology [Zurich], Ludwig-Maximilians-Universität München, Johannes Gutenberg - Universität Mainz ( JGU ), Medical University of Vienna, Lymphopoïèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Johannes Gutenberg - University of Mainz ( JGU ), Processus de Transfert et d'Echanges dans l'Environnement - EA 3819 ( PROTEE ), Université de Toulon ( UTLN ), Universita degli studi di Genova, Cossarizza, Andrea, Chang, Hyun-Dong, Radbruch, Andrea, Akdis, Mübeccel, Andrä, Immanuel, Annunziato, Francesco, Bacher, Petra, Barnaba, Vincenzo, Battistini, Luca, Bauer, Wolfgang M., Baumgart, Sabine, Becher, Burkhard, Beisker, Wolfgang, Berek, Claudia, Blanco, Alfonso, Borsellino, Giovanna, Boulais, Philip E., Brinkman, Ryan R., Büscher, Martin, Busch, Dirk H., Bushnell, Timothy P., Cao, Xuetao, Cavani, Andrea, Chattopadhyay, Pratip K., Cheng, Qingyu, Chow, Sue, Clerici, Mario, Cooke, Anne, Cosma, Antonio, Cosmi, Lorenzo, Cumano, Ana, Dang, Van Duc, Davies, Derek, De Biasi, Sara, Del Zotto, Genny, Della Bella, Silvia, Dellabona, Paolo, Deniz, Günnur, Dessing, Mark, Diefenbach, Andrea, Di Santo, Jame, Dieli, Francesco, Dolf, Andrea, Donnenberg, Vera S., Dörner, Thoma, Ehrhardt, Götz R. A., Endl, Elmar, Engel, Pablo, Engelhardt, Britta, Esser, Charlotte, Everts, Bart, Dreher, Anita, Falk, Christine S., Fehniger, Todd A., Filby, Andrew, Fillatreau, Simon, Follo, Marie, Förster, Irmgard, Foster, John, Foulds, Gemma A., Frenette, Paul S., Galbraith, David, Garbi, Natalio, García-Godoy, Maria Dolore, Geginat, Jen, Ghoreschi, Kamran, Gibellini, Lara, Goettlinger, Christoph, Goodyear, Carl S., Gori, Andrea, Grogan, Jane, Gross, Mor, Grützkau, Andrea, Grummitt, Daryl, Hahn, Jona, Hammer, Quirin, Hauser, Anja E., Haviland, David L., Hedley, David, Herrera, Guadalupe, Herrmann, Martin, Hiepe, Falk, Holland, Tristan, Hombrink, Pleun, Houston, Jessica P., Hoyer, Bimba F., Huang, Bo, Hunter, Christopher A., Iannone, Anna, Jäck, Hans-Martin, Jávega, Beatriz, Jonjic, Stipan, Juelke, Kerstin, Jung, Steffen, Kaiser, Toralf, Kalina, Toma, Keller, Baerbel, Khan, Srijit, Kienhöfer, Deborah, Kroneis, Thoma, Kunkel, Désirée, Kurts, Christian, Kvistborg, Pia, Lannigan, Joanne, Lantz, Olivier, Larbi, Ani, LeibundGut-Landmann, Salome, Leipold, Michael D., Levings, Megan K., Litwin, Virginia, Liu, Yanling, Lohoff, Michael, Lombardi, Giovanna, Lopez, Lilly, Lovett-Racke, Amy, Lubberts, Erik, Ludewig, Burkhard, Lugli, Enrico, Maecker, Holden T., Martrus, Glòria, Matarese, Giuseppe, Maueröder, Christian, Mcgrath, Mairi, Mcinnes, Iain, Mei, Henrik E., Melchers, Fritz, Melzer, Susanne, Mielenz, Dirk, Mills, Kingston, Mirrer, David, Mjösberg, Jenny, Moore, Jonni, Moran, Barry, Moretta, Alessandro, Moretta, Lorenzo, Mosmann, Tim R., Müller, Susann, Müller, Werner, Münz, Christian, Multhoff, Gabriele, Munoz, Luis Enrique, Murphy, Kenneth M., Nakayama, Toshinori, Nasi, Milena, Neudörfl, Christine, Nolan, John, Nourshargh, Sussan, O'Connor, José-Enrique, Ouyang, Wenjun, Oxenius, Annette, Palankar, Raghav, Panse, Isabel, Peterson, Pärt, Peth, Christian, Petriz, Jordi, Philips, Daisy, Pickl, Winfried, Piconese, Silvia, Pinti, Marcello, Pockley, A. Graham, Podolska, Malgorzata Justyna, Pucillo, Carlo, Quataert, Sally A., Radstake, Timothy R. D. J., Rajwa, Bartek, Rebhahn, Jonathan A., Recktenwald, Diether, Remmerswaal, Ester B. M., Rezvani, Katy, Rico, Laura G., Robinson, J. Paul, Romagnani, Chiara, Rubartelli, Anna, Ruckert, Beate, Ruland, Jürgen, Sakaguchi, Shimon, Sala-de-Oyanguren, Francisco, Samstag, Yvonne, Sanderson, Sharon, Sawitzki, Birgit, Scheffold, Alexander, Schiemann, Matthia, Schildberg, Frank, Schimisky, Esther, Schmid, Stephan A., Schmitt, Steffen, Schober, Kilian, Schüler, Thoma, Schulz, Axel Ronald, Schumacher, Ton, Scotta, Cristiano, Shankey, T. Vincent, Shemer, Anat, Simon, Anna-Katharina, Spidlen, Josef, Stall, Alan M., Stark, Regina, Stehle, Christina, Stein, Merle, Steinmetz, Tobit, Stockinger, Hanne, Takahama, Yousuke, Tarnok, Attila, Tian, Zhigang, Toldi, Gergely, Tornack, Julia, Traggiai, Elisabetta, Trotter, Joe, Ulrich, Henning, van der Braber, Marlou, van Lier, René A. W., Veldhoen, Marcello, Vento-Asturias, Salvador, Vieira, Paulo, Voehringer, David, Volk, Hans-Dieter, von Volkmann, Konrad, Waisman, Ari, Walker, Rachael, Ward, Michael D., Warnatz, Klau, Warth, Sarah, Watson, James V., Watzl, Carsten, Wegener, Leonie, Wiedemann, Annika, Wienands, Jürgen, Willimsky, Gerald, Wing, Jame, Wurst, Peter, Yu, Liping, Yue, Alice, Zhang, Qianjun, Zhao, Yi, Ziegler, Susanne, Zimmermann, Jakob, Cossarizza, A., Chang, H., Radbruch, A., Akdis, M., Andrã¤, I., Annunziato, F., Bacher, P., Barnaba, V., Battistini, L., Bauer, W., Baumgart, S., Becher, B., Beisker, W., Berek, C., Blanco, A., Borsellino, G., Boulais, P., Brinkman, R., Bã¼scher, M., Busch, D., Bushnell, T., Cao, X., Cavani, A., Chattopadhyay, P., Cheng, Q., Chow, S., Clerici, M., Cooke, A., Cosma, A., Cosmi, L., Cumano, A., Dang, V., Davies, D., De Biasi, S., Del Zotto, G., Della Bella, S., Dellabona, P., Deniz, G., Dessing, M., Diefenbach, A., Di Santo, J., Dieli, F., Dolf, A., Donnenberg, V., Dã¶rner, T., Ehrhardt, G., Endl, E., Engel, P., Engelhardt, B., Esser, C., Everts, B., Dreher, A., Falk, C., Fehniger, T., Filby, A., Fillatreau, S., Follo, M., Fã¶rster, I., Foster, J., Foulds, G., Frenette, P., Galbraith, D., Garbi, N., GarcÃa-Godoy, M., Geginat, J., Ghoreschi, K., Gibellini, L., Goettlinger, C., Goodyear, C., Gori, A., Grogan, J., Gross, M., Grã¼tzkau, A., Grummitt, D., Hahn, J., Hammer, Q., Hauser, A., Haviland, D., Hedley, D., Herrera, G., Herrmann, M., Hiepe, F., Holland, T., Hombrink, P., Houston, J., Hoyer, B., Huang, B., Hunter, C., Iannone, A., Jã¤ck, H., Jã¡vega, B., Jonjic, S., Juelke, K., Jung, S., Kaiser, T., Kalina, T., Keller, B., Khan, S., Kienhã¶fer, D., Kroneis, T., Kunkel, D., Kurts, C., Kvistborg, P., Lannigan, J., Lantz, O., Larbi, A., LeibundGut-Landmann, S., Leipold, M., Levings, M., Litwin, V., Liu, Y., Lohoff, M., Lombardi, G., Lopez, L., Lovett-Racke, A., Lubberts, E., Ludewig, B., Lugli, E., Maecker, H., Martrus, G., Matarese, G., Mauerã¶der, C., Mcgrath, M., Mcinnes, I., Mei, H., Melchers, F., Melzer, S., Mielenz, D., Mills, K., Mirrer, D., Mjã¶sberg, J., Moore, J., Moran, B., Moretta, A., Moretta, L., Mosmann, T., Mã¼ller, S., Mã¼ller, W., Mã¼nz, C., Multhoff, G., Munoz, L., Murphy, K., Nakayama, T., Nasi, M., Neudã¶rfl, C., Nolan, J., Nourshargh, S., O'Connor, J., Ouyang, W., Oxenius, A., Palankar, R., Panse, I., Peterson, P., Peth, C., Petriz, J., Philips, D., Pickl, W., Piconese, S., Pinti, M., Pockley, A., Podolska, M., Pucillo, C., Quataert, S., Radstake, T., Rajwa, B., Rebhahn, J., Recktenwald, D., Remmerswaal, E., Rezvani, K., Rico, L., Robinson, J., Romagnani, C., Rubartelli, A., Ruckert, B., Ruland, J., Sakaguchi, S., Sala-de-Oyanguren, F., Samstag, Y., Sanderson, S., Sawitzki, B., Scheffold, A., Schiemann, M., Schildberg, F., Schimisky, E., Schmid, S., Schmitt, S., Schober, K., Schã¼ler, T., Schulz, A., Schumacher, T., Scotta, C., Shankey, T., Shemer, A., Simon, A., Spidlen, J., Stall, A., Stark, R., Stehle, C., Stein, M., Steinmetz, T., Stockinger, H., Takahama, Y., Tarnok, A., Tian, Z., Toldi, G., Tornack, J., Traggiai, E., Trotter, J., Ulrich, H., van der Braber, M., van Lier, R., Veldhoen, M., Vento-Asturias, S., Vieira, P., Voehringer, D., Volk, H., von Volkmann, K., Waisman, A., Walker, R., Ward, M., Warnatz, K., Warth, S., Watson, J., Watzl, C., Wegener, L., Wiedemann, A., Wienands, J., Willimsky, G., Wing, J., Wurst, P., Liping, Y., Yue, A., Zhang, Q., Zhao, Y., Ziegler, S., and Zimmermann, J.
Subjects: 0301 basic medicine, T-Lymphocytes, Cell Separation, T cell precursors, 0302 clinical medicine, Immunophenotyping, Human lymphopoiesis, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Non-U.S. Gov't, Immunologic Technique, medicine.diagnostic_test, Research Support, Non-U.S. Gov't, virus diseases, hemic and immune systems, False Positive Reaction, Cell sorting, Flow Cytometry, natural killer and innate lymphoid cells differentiation, 3. Good health, Research Design, [SDV.IMM]Life Sciences [q-bio]/Immunology, Human, Quality Control, medicine.drug_class, Immunology, Animals, Cell Proliferation, DNA, False Positive Reactions, Humans, RNA, Software, Guidelines as Topic, Immunologic Techniques, chemical and pharmacologic phenomena, Computational biology, Biology, Monoclonal antibody, Research Support, Article, Flow cytometry, N.I.H, 03 medical and health sciences, Immune system, Research Support, N.I.H., Extramural, medicine, early lymphoid progenitors, Journal Article, Mass cytometry, IMUNOLOGIA, Animal, Extramural, B cell ontogeny, 030104 developmental biology, T-Lymphocyte, Cytometry, 030215 immunology
Abstract: The marriage between immunology and cytometry is one of the most stable and productive in the recent history of science. A rapid search in PubMed shows that, as of July 2017, using “flow cytometry immunology” as a search term yields more than 68 000 articles, the first of which, interestingly, is not about lymphocytes. It might be stated that, after a short engagement, the exchange of the wedding rings between immunology and cytometry officially occurred when the idea to link fluorochromes to monoclonal antibodies came about. After this, recognizing different types of cells became relatively easy and feasible not only by using a simple fluorescence microscope, but also by a complex and sometimes esoteric instrument, the flow cytometer that is able to count hundreds of cells in a single second, and can provide repetitive results in a tireless manner. Given this, the possibility to analyse immune phenotypes in a variety of clinical conditions has changed the use of the flow cytometer, which was incidentally invented in the late 1960s to measure cellular DNA by using intercalating dyes, such as ethidium bromide. The epidemics of HIV/AIDS in the 1980s then gave a dramatic impulse to the technology of counting specific cells, since it became clear that the quantification of the number of peripheral blood CD4+ T cells was crucial to follow the course of the infection, and eventually for monitoring the therapy. As a consequence, the development of flow cytometers that had to be easy-to-use in all clinical laboratories helped to widely disseminate this technology. Nowadays, it is rare to find an immunological paper or read a conference abstract in which the authors did not use flow cytometry as the main tool to dissect the immune system and identify its fine and complex functions. Of note, recent developments have created the sophisticated technology of mass cytometry, which is able to simultaneously identify dozens of molecules at the single cell level and allows us to better understand the complexity and beauty of the immune system.
Published: 2017

47. Functional analysis via standardized whole-blood stimulation systems defines the boundaries of a healthy immune response to complex stimuli

Author: Ivo Gomperts-Boneca, Ludovic Deriano, Spencer L. Shorte, Annick Dubois, Anavaj Sakuntabhai, Claude Leclerc, Caroline Demangel, Ana Cumano, Lluis Quintana-Murci, Matthew L. Albert, Antonio A. Freitas, Antoine Toubert, Lars Rogge, Manfred Schmolz, Gérard Eberl, Vincent Rouilly, Valentina Libri, Alejandra Urrutia, James P. Di Santo, Eric Tartour, Marie-Noëlle Ungeheuer, Françoise Dromer, Hugo Mouquet, Olivier Schwartz, Benoit Beitz, Mikael David, Olivier Lantz, Stéphanie Thomas, Ivo G. Boneca, Philippe Bousso, Laurent Abel, Vassili Soumelis, Cécile Delval, Darragh Duffy, Benno Schwikowski, Frédéric Tangy, Serge Hercberg, Jost Enninga, Milena Hasan, Samuel S.T. LaBrie, Sandra Pellegrini, Aurélie Bisiaux, Stanislas Pol, Marc Daëron, Andrés Alcover, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Centre d'Immunologie Humaine (CIH), Substances Lichéniques et Photoprotection, Université de Rennes (UR), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules Dendritiques, Myriad rules based medicine, Chambre Régionale d'Agriculture des Pays de la Loire, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Laboratoire de géographie physique : Environnements Quaternaires et Actuels (LGP), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Département d'Immunologie - Department of Immunology, Immunorégulation, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Laboratory of Cellular Physiology and Immunology and Chris Browne Center, Rockefeller University [New York], St. Giles Laboratory of Human Genetics of Infectious Diseases, Laboratory of Human Genetics of Infectious Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Dynamiques des Réponses Immunes, Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie de l'Infection - Immunobiology of Infection, Département de Génomes et Génétique - Department of Genomes and Genetics, Mycologie moléculaire, Centre National de Référence Mycologie et Antifongiques-Mycologie Moléculaire (CNRMA), Microenvironnement et Immunité - Microenvironment and Immunity, Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de formation en masso-kinésithérapie (IFMK Brest), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Réponse humorale aux pathogènes, Signalisation des Cytokines - Cytokine Signaling, Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Centre de recherche sur les liens sociaux (CERLIS - UMR 8070), Université Sorbonne Nouvelle - Paris 3-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Biologie systémique - Systems Biology, Imagopole (CITECH), Laboratoire d'Immunologie Clinique, Institut Curie [Paris], Génomique virale et vaccination, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), This work benefited from support of the French government’s Invest in the Future Program, managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01). We also acknowledge A. Pugsley for his support in obtaining funding and the logistical aspects of initiating the project, Milieu Intérieur Consortium (32 collaborateurs) : Abel L, Alcover A, Bousso P, Cumano A, Daëron M, Delval C, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Freitas A, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Pellegrini S, Pol S, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Paris 13 (UP13)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Translationnelle ( CRT ), Centre d'Immunologie Humaine ( CIH ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Centre d'Immunologie et de Maladies Infectieuses ( CIMI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie et Génétique de la Paroi bactérienne, Laboratoire de géographie physique ( LGP ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Département d'Immunologie, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), rockefeller university, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Biologie Cellulaire des Lymphocytes, Lymphopoïèse, Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité, Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Immunobiologie de l'Infection, Département de Génomes et Génétique, Centre National de Référence Mycologie et Antifongiques-Mycologie Moléculaire ( CNRMA ), Microenvironnement et Immunité, Dynamique des Interactions Hôte-Pathogène, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle ( CRESS - U1153 ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de formation en masso-kinésithérapie ( IFMK Brest ), Université de Brest ( UBO ) -Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Signalisation des Cytokines, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Génétique fonctionnelle des Maladies infectieuses, CERLIS - Centre de recherche sur les liens sociaux - UMR 8070 ( CERLIS - UMR 8070 ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Sorbonne Nouvelle - Paris 3, Biologie systémique, Imagopole ( CITECH ), Institut Curie, Institut Curie-Institut Curie, Cytokines et Immunologie des Tumeurs Humaines ( U753 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources ( ICAReB ), ANR : 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE ( 2010 ), Centre de Recherche Translationnelle (CRT), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Panthéon-Sorbonne (UP1), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and ANR: 10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010)
Subjects: Chemokine, MESH : Cytokines, MESH : Antigens, Disease, MESH : Monitoring, Immunologic, Adaptive Immunity, 0302 clinical medicine, Immunophenotyping, Reference Values, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, MESH: Monitoring, Immunologic, MESH: Healthy Volunteers, 0303 health sciences, MESH: Cytokines, biology, MESH: Reference Values, MESH : Immunity, Innate, Healthy Volunteers, 3. Good health, MESH: Reproducibility of Results, Infectious Diseases, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Antigens, MESH: Immunity, Innate, Inflammation Mediators, Functional analysis (psychology), Whole blood stimulation, MESH : Adaptive Immunity, Immunology, MESH: Inflammation Mediators, MESH : Reference Values, MESH : Inflammation Mediators, 03 medical and health sciences, Immune system, Immunity, Monitoring, Immunologic, Humans, Antigens, 030304 developmental biology, MESH : Healthy Volunteers, MESH: Humans, MESH : Reproducibility of Results, MESH : Humans, Reproducibility of Results, Immunity, Innate, Reference values, biology.protein, MESH: Adaptive Immunity, 030215 immunology
Abstract: International audience; Standardization of immunophenotyping procedures has become a high priority. We have developed a suite of whole-blood, syringe-based assay systems that can be used to reproducibly assess induced innate or adaptive immune responses. By eliminating preanalytical errors associated with immune monitoring, we have defined the protein signatures induced by (1) medically relevant bacteria, fungi, and viruses; (2) agonists specific for defined host sensors; (3) clinically employed cytokines; and (4) activators of T cell immunity. Our results provide an initial assessment of healthy donor reference values for induced cytokines and chemokines and we report the failure to release interleukin-1α as a common immunological phenotype. The observed naturally occurring variation of the immune response may help to explain differential susceptibility to disease or response to therapeutic intervention. The implementation of a general solution for assessment of functional immune responses will help support harmonization of clinical studies and data sharing.
Published: 2014

48. Risk of tumorigenicity in mesenchymal stromal cell-based therapies--bridging scientific observations and regulatory viewpoints

Author: Paula Salmikangas, Olivier Lantz, Marcel Kwa, Peter Ahnert, Arnaud Foussat, Sophie Lucas-Samuel, Lisbeth Barkholt, Karin Tarte, Romaldas Mačiulaitis, Christian K. Schneider, Gérard Tachdjian, Dirk Büscher, Luc Sensebé, Tiina Palomäki, Lucie Tosca, Veronika Jekerle, Willem E. Fibbe, Egbert Flory, Louise Bisset, Cell products working party (CPWP), European Medicines Agency, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], GRI-CEL, Leiden University Medical Center (LUMC), TxCell, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Lithuanian university of health sciences, Institute of physiology and pharmacology, Danish health and medicines authority, STROMALab, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig-Universität Leipzig, Universiteit Leiden, Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement Français du Sang-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Cell products working party ( CPWP ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Etablissement Français du Sang-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)
Subjects: Cancer Research, Pathology, medicine.medical_specialty, Stromal cell, Carcinogenesis, Immunology, Cell Culture Techniques, Bone Marrow Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, mesenchymal, Mesenchymal Stem Cell Transplantation, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Immunology and Allergy, Genetics (clinical), Cell Proliferation, 030304 developmental biology, 0303 health sciences, Transplantation, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, business.industry, Mesenchymal stem cell, Cell Differentiation, Mesenchymal Stem Cells, Cell Biology, cell, Viewpoints, 3. Good health, Adipose Tissue, Oncology, 030220 oncology & carcinogenesis, tumorigenicity, stromal, business
Abstract: International audience; In the past decade, the therapeutic value of mesenchymal stromal cells (MSCs) has been studied in various indications, thereby taking advantage of their immunosuppressive properties. Easy procurement from bone marrow, adipose tissue or other sources and conventional in vitro expansion culture have made their clinical use attractive. Bridging the gap between current scientific knowledge and regulatory prospects on the transformation potential and possible tumorigenicity of MSCs, the Cell Products Working Party and the Committee for Advanced Therapies organized a meeting with leading European experts in the field of MSCs. This meeting elucidated the risk of potential tumorigenicity related to MSC-based therapies from two angles: the scientific perspective and the regulatory point of view. The conclusions of this meeting, including the current regulatory thinking on quality, nonclinical and clinical aspects for MSCs, are presented in this review, leading to a clearer way forward for the development of such products.
Published: 2013

49. MAIT Cell Recognition of MR1 on Bacterially Infected and Uninfected Cells

Author: John W. Kappler, Thierry Mallevaey, Mary H. Young, Frances Crawford, Laurent Gapin, Ted H. Hansen, Philippa Marrack, James P. Scott-Browne, Olivier Lantz, Shouxiong Huang, and Lance U'Ren
Subjects: Models, Molecular, Anatomy and Physiology, Protein Conformation, Lymphocyte, lcsh:Medicine, Antigen Processing and Recognition, Mice, 0302 clinical medicine, T-Lymphocyte Subsets, Immune Physiology, Molecular Cell Biology, lcsh:Science, 0303 health sciences, education.field_of_study, B-Lymphocytes, Multidisciplinary, T Cells, Ligand (biochemistry), medicine.anatomical_structure, Medicine, Cellular Types, Endopeptidase K, Research Article, Protein Binding, Immune Cells, Population, Immunology, Receptors, Antigen, T-Cell, Biology, Cell Line, Minor Histocompatibility Antigens, 03 medical and health sciences, Antigen, MHC class I, medicine, Escherichia coli, Animals, Antigens, Antigen-presenting cell, education, 030304 developmental biology, Antigens, Bacterial, T-cell receptor, lcsh:R, Histocompatibility Antigens Class I, Lipid Metabolism, Molecular biology, Coculture Techniques, Cell culture, Mutagenesis, Mutation, Proteolysis, biology.protein, lcsh:Q, 030215 immunology
Abstract: Mucosal-associated invariant T cells are a unique population of T cells that express a semi-invariant αβ TCR and are restricted by the MHC class I-related molecule MR1. MAIT cells recognize uncharacterized ligand(s) presented by MR1 through the cognate interaction between their TCR and MR1. To understand how the MAIT TCR recognizes MR1 at the surface of APCs cultured both with and without bacteria, we undertook extensive mutational analysis of both the MAIT TCR and MR1 molecule. We found differential contribution of particular amino acids to the MAIT TCR-MR1 interaction based upon the presence of bacteria, supporting the hypothesis that the structure of the MR1 molecules with the microbial-derived ligand(s) differs from the one with the endogenous ligand(s). Furthermore, we demonstrate that microbial-derived ligand(s) is resistant to proteinase K digestion and does not extract with common lipids, suggesting an unexpected class of antigen(s) might be recognized by this unique lymphocyte population.
Published: 2013

50. Human iNKT and MAIT cells exhibit a PLZF-dependent proapoptotic propensity that is counterbalanced by XIAP

Author: Sophie Sibéril, Capucine Picard, Emmanuel Martin, Stéphane Gérart, Sylvain Latour, Olivier Lantz, Alain Fischer, Christelle Lenoir, and Claire Aguilar
Subjects: T cell, Receptors, Antigen, T-Cell, alpha-beta, Immunology, Kruppel-Like Transcription Factors, Apoptosis, X-Linked Inhibitor of Apoptosis Protein, Mucosal associated invariant T cell, Inhibitor of apoptosis, Biochemistry, Article, 03 medical and health sciences, 0302 clinical medicine, Antigen, T-Lymphocyte Subsets, medicine, Humans, Promyelocytic Leukemia Zinc Finger Protein, Lymphocyte Count, Caspase, 030304 developmental biology, 0303 health sciences, biology, Cell Biology, Hematology, Natural killer T cell, XIAP, Cell biology, medicine.anatomical_structure, Phenotype, Gene Expression Regulation, biology.protein, Natural Killer T-Cells, Apoptosis Regulatory Proteins, 030215 immunology
Abstract: Invariant natural killer (iNKT) T cells and mucosal-associated invariant T (MAIT) cells represent peculiar T-lymphocyte subpopulations with innate-like properties that differ from conventional T cells. iNKT are reduced in the primary immunodeficiency caused by mutations in the X-linked inhibitor of apoptosis (XIAP). By studying the mechanism of this depletion, we herein report that iNKT cells exhibit a high susceptibility to apoptosis that is not observed with conventional T cells. Elevated expression of caspases 3 and 7 accounts for the proapoptotic phenotype of iNKT cells, which is inhibited by XIAP although it exerts a moderate effect in conventional T cells. Similarly, MAIT cells exhibit a proapoptotic propensity with elevated expression of activated caspases and are decreased in XIAP-deficient individuals. Knockdown of the transcription factor PLZF/ZBTB-16, which is involved in the effector program of iNKT cells, diminishes their proapoptotic phenotype. Conversely, overexpression of PLZF/ZBTB-16 in conventional T cells leads to a proapoptotic phenotype. Our findings identify a previously unknown pathway of regulation of innate-like T-cell homeostasis depending on XIAP and PLZF. The proapoptotic feature of iNKT cells also gives a reliable explanation of their exhaustion observed in different human conditions including the XIAP immunodeficiency.
Published: 2012

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