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3. Polarized mitochondria as guardians of NK cell fitness

Author

Surace, Laura, Doisne, Jean-Marc, Escoll, Pedro, Marie, Solenne, Dardalhon, Valerie, Croft, Carys, Thaller, Anna, Topazio, Davide, Sparaneo, Angelo, Cama, Antonia, Musumeci, Olimpia, d'Ecclesia, Aurelio, Buchrieser, Carmen, Taylor, Naomi, and Di Santo, James P.

Published
2021
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4. Standardized high‐dimensional spectral cytometry protocol and panels for whole blood immune phenotyping in clinical and translational studies

Author

Dott, Tom, primary, Culina, Slobodan, additional, Chemali, Rene, additional, Ait Mansour, Cedric, additional, Dubois, Florian, additional, Jagla, Bernd, additional, Doisne, Jean Marc, additional, Rogge, Lars, additional, Huetz, François, additional, Jönsson, Friederike, additional, Commere, Pierre‐Henri, additional, Santo, James Di, additional, Terrier, Benjamin, additional, Quintana‐Murci, Lluis, additional, Duffy, Darragh, additional, Hasan, Milena, additional, and Consortium, Milieu Intérieur, additional

Published
2023
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5. A human immune system (HIS) mouse model that dissociates roles for mouse and human FcR+ cells during antibody‐mediated immune responses

Author

Thaller, Anna Louisa, primary, Jönsson, Friederike, additional, Fiquet, Oriane, additional, Marie, Solenne, additional, Doisne, Jean‐Marc, additional, Girelli‐Zubani, Giulia, additional, Eri, Toshiki, additional, Fernandes, Priyanka, additional, Tatirovsky, Evgeny, additional, Langa‐Vives, Francina, additional, Bruhns, Pierre, additional, Strick‐Marchand, Hélène, additional, and Di Santo, James P., additional

Published
2023
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6. Standardized high‐dimensional spectral cytometry protocol and panels for whole blood immune phenotyping in clinical and translational studies.

Author

Dott, Tom, Culina, Slobodan, Chemali, Rene, Mansour, Cedric Ait, Dubois, Florian, Jagla, Bernd, Doisne, Jean Marc, Rogge, Lars, Huetz, François, Jönsson, Friederike, Commere, Pierre‐Henri, Di Santo, James, Terrier, Benjamin, Quintana‐Murci, Lluis, Duffy, Darragh, Hasan, Milena, Abel, Laurent, Alcover, Andres, Aschard, Hugues, and Bousso, Philippe

Abstract

Flow cytometry is the method of choice for immunophenotyping in the context of clinical, translational, and systems immunology studies. Among the latter, the Milieu Intérieur (MI) project aims at defining the boundaries of a healthy immune response to identify determinants of immune response variation. MI used immunophenotyping of a 1000 healthy donor cohort by flow cytometry as a principal outcome for immune variance at steady state. New generation spectral cytometers now enable high‐dimensional immune cell characterization from small sample volumes. Therefore, for the MI 10‐year follow up study, we have developed two high‐dimensional spectral flow cytometry panels for deep characterization of innate and adaptive whole blood immune cells (35 and 34 fluorescent markers, respectively). We have standardized the protocol for sample handling, staining, acquisition, and data analysis. This approach enables the reproducible quantification of over 182 immune cell phenotypes at a single site. We have applied the protocol to discern minor differences between healthy and patient samples and validated its value for application in immunomonitoring studies. Our protocol is currently used for characterization of the impact of age and environmental factors on peripheral blood immune phenotypes of >400 donors from the initial MI cohort. [ABSTRACT FROM AUTHOR]

Published
2024
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7. A human immune system (HIS) mouse model that dissociates roles for mouse and human FcR+ cells during antibody‐mediated immune responses.

Author

Thaller, Anna Louisa, Jönsson, Friederike, Fiquet, Oriane, Marie, Solenne, Doisne, Jean‐Marc, Girelli‐Zubani, Giulia, Eri, Toshiki, Fernandes, Priyanka, Tatirovsky, Evgeny, Langa‐Vives, Francina, Bruhns, Pierre, Strick‐Marchand, Hélène, and Di Santo, James P.

Subjects
ANTIBODY-dependent cell cytotoxicity, IMMUNE response, LABORATORY mice, IMMUNE system, PHAGOCYTOSIS, ANIMAL disease models, ECULIZUMAB
Abstract

Human immune system (HIS) mice provide a model to study human immune responses in vivo. Currently available HIS mouse models may harbor mouse Fc Receptor (FcR)‐expressing cells that exert potent effector functions following administration of human Ig. Previous studies showed that the ablation of the murine FcR gamma chain (FcR‐γ) results in loss of antibody‐dependent cellular cytotoxicity and antibody‐dependent cellular phagocytosis in vivo. We created a new FcR‐γ‐deficient HIS mouse model to compare host (mouse) versus graft (human) effects underlying antibody‐mediated immune responses in vivo. FcR‐γ‐deficient HIS recipients lack expression and function of mouse activating FcRs and can be stably and robustly reconstituted with human immune cells. By screening blood B‐cell depletion by rituximab Ig variants, we found that human FcγRs‐mediated IgG1 effects, whereas mouse activating FcγRs were dominant in IgG4 effects. Complement played a role as an IgG1 variant (IgG1 K322A) lacking complement binding activity was largely ineffective. Finally, we provide evidence that FcγRIIIA on human NK cells could mediate complement‐independent B‐cell depletion by IgG1 K322A. We anticipate that our FcR‐γ‐deficient HIS model will help clarify mechanisms of action of exogenous administered human antibodies in vivo. [ABSTRACT FROM AUTHOR]

Published
2023
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8. Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Author

Rosain, Jérémie, primary, Neehus, Anna-Lena, additional, Manry, Jérémy, additional, Yang, Rui, additional, Le Pen, Jérémie, additional, Daher, Wassim, additional, Liu, Zhiyong, additional, Chan, Yi-Hao, additional, Tahuil, Natalia, additional, Türel, Özden, additional, Bourgey, Mathieu, additional, Ogishi, Masato, additional, Doisne, Jean-Marc, additional, Izquierdo, Helena M., additional, Shirasaki, Takayoshi, additional, Le Voyer, Tom, additional, Guérin, Antoine, additional, Bastard, Paul, additional, Moncada-Vélez, Marcela, additional, Han, Ji Eun, additional, Khan, Taushif, additional, Rapaport, Franck, additional, Hong, Seon-Hui, additional, Cheung, Andrew, additional, Haake, Kathrin, additional, Mindt, Barbara C., additional, Pérez, Laura, additional, Philippot, Quentin, additional, Lee, Danyel, additional, Zhang, Peng, additional, Rinchai, Darawan, additional, Al Ali, Fatima, additional, Ahmad Ata, Manar Mahmoud, additional, Rahman, Mahbuba, additional, Peel, Jessica N., additional, Heissel, Søren, additional, Molina, Henrik, additional, Kendir-Demirkol, Yasemin, additional, Bailey, Rasheed, additional, Zhao, Shuxiang, additional, Bohlen, Jonathan, additional, Mancini, Mathieu, additional, Seeleuthner, Yoann, additional, Roelens, Marie, additional, Lorenzo, Lazaro, additional, Soudée, Camille, additional, Paz, María Elvira Josefina, additional, González, María Laura, additional, Jeljeli, Mohamed, additional, Soulier, Jean, additional, Romana, Serge, additional, L’Honneur, Anne-Sophie, additional, Materna, Marie, additional, Martínez-Barricarte, Rubén, additional, Pochon, Mathieu, additional, Oleaga-Quintas, Carmen, additional, Michev, Alexandre, additional, Migaud, Mélanie, additional, Lévy, Romain, additional, Alyanakian, Marie-Alexandra, additional, Rozenberg, Flore, additional, Croft, Carys A., additional, Vogt, Guillaume, additional, Emile, Jean-François, additional, Kremer, Laurent, additional, Ma, Cindy S., additional, Fritz, Jörg H., additional, Lemon, Stanley M., additional, Spaan, András N., additional, Manel, Nicolas, additional, Abel, Laurent, additional, MacDonald, Margaret R., additional, Boisson-Dupuis, Stéphanie, additional, Marr, Nico, additional, Tangye, Stuart G., additional, Di Santo, James P., additional, Zhang, Qian, additional, Zhang, Shen-Ying, additional, Rice, Charles M., additional, Béziat, Vivien, additional, Lachmann, Nico, additional, Langlais, David, additional, Casanova, Jean-Laurent, additional, Gros, Philippe, additional, and Bustamante, Jacinta, additional

Published
2023
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13. Dichotomous metabolic networks govern human ILC2 proliferation and function

Author

Surace, Laura, primary, Doisne, Jean-Marc, additional, Croft, Carys A., additional, Thaller, Anna, additional, Escoll, Pedro, additional, Marie, Solenne, additional, Petrosemoli, Natalia, additional, Guillemot, Vincent, additional, Dardalhon, Valerie, additional, Topazio, Davide, additional, Cama, Antonia, additional, Buchrieser, Carmen, additional, Taylor, Naomi, additional, Amit, Ido, additional, Musumeci, Olimpia, additional, and Di Santo, James P., additional

Published
2021
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15. CD116+ fetal precursors migrate to the perinatal lung and give rise to human alveolar macrophages

Author

Evren, Elza, Ringqvist, Emma, Doisne, Jean-Marc, Thaller, Anna, Sleiers, Natalie, Flavell, Richard, Di Santo, James, Willinger, Tim, Karolinska Institutet [Stockholm], Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Department of Immunobiology [New Haven, CT, USA] (Yale School of Medicine), Yale University [New Haven], Howard Hughes Medical Institute (HHMI), This work was supported by a faculty-funded career position at Karolinska Institutet (2-1060/2018), a Karolinska Institutet Research Foundation Grant (2020-01438), a Junior Investigator and Junior Project Research Grant from the Center for Innovative Medicine financed by Region Stockholm (2-538/2014, 20190152), as well as project grants from the Swedish Research Council (2015-02413, 2019-01099), the Swedish Heart-Lung Foundation (20190198), Petrus och Augusta Hedlunds Stiftelse (M-2021-1568), and the SciLifeLab National COVID-19 Research Program, financed by the Knut and Alice Wallenberg Foundation (C19PI:G:012) to T. Willinger. E. Evren was supported by a scholarship from the Royal Swedish Academy of Sciences (BS2021-0030). A. Thaller was supported by the European Union’s Horizon 2020 research and innovation program (H2020 Marie Skłodowska-Curie Actions grant 765104). R.A. Flavell is an investigator of the Howard Hughes Medical Institute., and European Project: 765104,MATURE-NK

Subjects
MESH: Cell Differentiation, MESH: Macrophages, Alveolar, MESH: Gene Expression, MESH: Immunophenotyping, MESH: Mice, Transgenic, Genes, myb, [SDV]Life Sciences [q-bio], Innate Immunity and Inflammation, Gene Expression, Mice, Transgenic, MESH: Stem Cells, Article, Immunophenotyping, Mice, Fetus, MESH: Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Cell Movement, Macrophages, Alveolar, Animals, Humans, MESH: Animals, MESH: Lung, MESH: Mice, MESH: Cell Movement, Lung, MESH: Genes, myb, MESH: Humans, Stem Cells, MESH: Fetus, MESH: Immunohistochemistry, Cell Differentiation, Mucosal Immunology, respiratory system, Immunohistochemistry, Hematopoiesis, Liver, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, MESH: Biomarkers, Biomarkers, MESH: Liver
Abstract

Evren et al. identify CD116+ fetal liver cells as precursors of human alveolar macrophages in early life and determine the impact of cell origin on lung macrophage identity and function in the human context with a unique in vivo model., Despite their importance in lung health and disease, it remains unknown how human alveolar macrophages develop early in life. Here we define the ontogeny of human alveolar macrophages from embryonic progenitors in vivo, using a humanized mouse model expressing human cytokines (MISTRG mice). We identified alveolar macrophage progenitors in human fetal liver that expressed the GM-CSF receptor CD116 and the transcription factor MYB. Transplantation experiments in MISTRG mice established a precursor–product relationship between CD34−CD116+ fetal liver cells and human alveolar macrophages in vivo. Moreover, we discovered circulating CD116+CD64−CD115+ macrophage precursors that migrated from the liver to the lung. Similar precursors were present in human fetal lung and expressed the chemokine receptor CX3CR1. Fetal CD116+CD64− macrophage precursors had a proliferative gene signature, outcompeted adult precursors in occupying the perinatal alveolar niche, and developed into functional alveolar macrophages. The discovery of the fetal alveolar macrophage progenitor advances our understanding of human macrophage origin and ontogeny., Graphical Abstract

Published
2021

17. CXCR3 and CXCR5 are highly expressed in HIV‐1‐specific CD8 central memory T cells from infected patients

Author

Olivo, Anaëlle, primary, Lécuroux, Camille, additional, Bitu, Marie, additional, Avettand‐Fenoel, Véronique, additional, Boufassa, Faroudy, additional, Essat, Asma, additional, Meyer, Laurence, additional, Doisne, Jean‐Marc, additional, Favier, Benoit, additional, Vaslin, Bruno, additional, Schlecht‐Louf, Géraldine, additional, Noël, Nicolas, additional, Goujard, Cécile, additional, Lambotte, Olivier, additional, and Bourgeois, Christine, additional

Published
2021
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19. Metabolic alterations in Hurley stage 1 Hidradenitis Suppurativa

Author

Delage, Maïa, Guenin-Macé, Laure, Morel, Jean-David, Doisne, Jean-Marc, Schiavo, Angèle, Ungeheuer, Marie-Noëlle, Lam, Thi, Join-Lambert, Olivier, Santo, James, Nassif, Aude, Demangel, Caroline, Centre Médical de l'Institut Pasteur, Institut Pasteur [Paris], Immunobiologie de l'Infection - Immunobiology of Infection, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité Innée - Innate Immunity, Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Service de Microbiologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Groupe de Recherche sur l'Adaptation Microbienne (GRAM 2.0), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Mzembaba, Sandy, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]

Subjects
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2020

20. STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice

Author

Bennion, Brock, Croft, Carys, Ai, Teresa, Qian, Wei, Menos, Amber, Miner, Cathrine, Frémond, Marie-Louis, Doisne, Jean-Marc, Andhey, Prabhakar, Platt, Derek, Bando, Jennifer, Wang, Erin, Luksch, Hella, Molina, Thierry, Roberson, Elisha, Artyomov, Maxim, Rösen-Wolff, Angela, Colonna, Marco, Rieux-Laucat, Frédéric, Di Santo, James, Neven, Bénédicte, Miner, Jonathan, Croft, Carys Anne, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Appel à projets générique - Etude de familles multiplex de lupus pour l'identification de nouveaux gènes à fort impact phénotypique : de la découvertes des gènes à leurs fonctions - - Lumugene2014 - ANR-14-CE14-0026 - Appel à projets générique - VALID, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Sorbonne Paris Cité, Paris, France, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Université Paris Cité (UPCité), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), We thank the Hope Center Transgenic Vectors Core for assistance with generation of transgenic mice and the Washington University Morphology and Imaging Core for assistance with tissue processing and staining. D.J.P. is supported by the Washington University Chancellors Graduate Fellowship Program and the Initiative to Maximize Student Development. The Miner laboratory is supported by grants from the NIH (K08 AR070918 and R01 AI143982). RNA sequencing data analysis was supported by the WUSTL Rheumatic Diseases Research Resource-based Core (E.D.O.R., P30-AR073752). Single-cell RNA-seq data were generated at the Washington University GTAC MGI sequencing core, which is partially supported by NCI grant P30 CA91842 (Siteman Cancer Center) and ICTS/CTSA grant UL1 TR002345. C.A.C. is part of the Pasteur-Paris University (PPU) International PhD Program that received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement 665807 and from the Labex Revive, Institut Pasteur. The study was also supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), by a government grant managed by the Agence National de la Recherche as part of the 'Investment for the Future' program (ANR-10-IAHU-01), and by an AAPG grant from the Agence National de la Recherche (ANR-14-CE14-0026-01 'Lumugene' to F.R.-L.). The Rösen-Wolff laboratory is supported by the German Research Foundation (TRR237,B18)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-CE14-0026,Lumugene,Etude de familles multiplex de lupus pour l'identification de nouveaux gènes à fort impact phénotypique : de la découvertes des gènes à leurs fonctions(2014), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Lymphoid Tissue, Organogenesis, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Article, Mice, lymphoid tissue organogenesis, Animals, Lymphocytes, Peyer's patch, lcsh:QH301-705.5, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Cell Differentiation, T-Lymphocytes, Helper-Inducer, lymphopoiesis, lymph node, Immunity, Innate, eye diseases, SAVI, lcsh:Biology (General), ILC, Gain of Function Mutation, innate lymphoid cell, Lymph Nodes, STING-associated vasculopathy with onset in infancy, LTi cell, STING
Abstract

International audience; STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer's patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4β7+ progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in RORγT-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. RORγT lineage-specific expression of STING gain-of-function also causes lung disease. Since RORγT is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice.

Published
2020

21. Polarized mitochondria as guardians of NK cell fitness

Author

Surace, Laura, primary, Doisne, Jean-Marc, additional, Escoll, Pedro, additional, Marie, Solenne, additional, Dardalhon, Valerie, additional, Croft, Carys, additional, Thaller, Anna, additional, Topazio, Davide, additional, Sparaneo, Angelo, additional, Cama, Antonia, additional, Musumeci, Olimpia, additional, d’Ecclesia, Aurelio, additional, Buchrieser, Carmen, additional, Taylor, Naomi, additional, and Di Santo, James P., additional

Published
2020
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22. Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria

Author

Yang, Rui, primary, Mele, Federico, additional, Worley, Lisa, additional, Langlais, David, additional, Rosain, Jérémie, additional, Benhsaien, Ibithal, additional, Elarabi, Houda, additional, Croft, Carys A., additional, Doisne, Jean-Marc, additional, Zhang, Peng, additional, Weisshaar, Marc, additional, Jarrossay, David, additional, Latorre, Daniela, additional, Shen, Yichao, additional, Han, Jing, additional, Ogishi, Masato, additional, Gruber, Conor, additional, Markle, Janet, additional, Al Ali, Fatima, additional, Rahman, Mahbuba, additional, Khan, Taushif, additional, Seeleuthner, Yoann, additional, Kerner, Gaspard, additional, Husquin, Lucas T., additional, Maclsaac, Julia L., additional, Jeljeli, Mohamed, additional, Errami, Abderrahmane, additional, Ailal, Fatima, additional, Kobor, Michael S., additional, Oleaga-Quintas, Carmen, additional, Roynard, Manon, additional, Bourgey, Mathieu, additional, El Baghdadi, Jamila, additional, Boisson-Dupuis, Stéphanie, additional, Puel, Anne, additional, Batteux, Fréderic, additional, Rozenberg, Flore, additional, Marr, Nico, additional, Pan-Hammarström, Qiang, additional, Bogunovic, Dusan, additional, Quintana-Murci, Lluis, additional, Carroll, Thomas, additional, Ma, Cindy S., additional, Abel, Laurent, additional, Bousfiha, Aziz, additional, Di Santo, James P., additional, Glimcher, Laurie H., additional, Gros, Philippe, additional, Tangye, Stuart G., additional, Sallusto, Federica, additional, Bustamante, Jacinta, additional, and Casanova, Jean-Laurent, additional

Published
2020
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23. Dysregulation of tryptophan catabolism at the host-skin microbiota interface in hidradenitis suppurativa

Author

Guenin-Macé, Laure, primary, Morel, Jean-David, additional, Doisne, Jean-Marc, additional, Schiavo, Angèle, additional, Boulet, Lysiane, additional, Mayau, Véronique, additional, Goncalves, Pedro, additional, Duchatelet, Sabine, additional, Hovnanian, Alain, additional, Bondet, Vincent, additional, Duffy, Darragh, additional, Ungeheuer, Marie-Noëlle, additional, Delage, Maïa, additional, Nassif, Aude, additional, Di Santo, James P., additional, and Demangel, Caroline, additional

Published
2020
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24. Immunomodulation of Selective Naive T Cell Functions by p110δ Inactivation Improves the Outcome of Mismatched Cell Transplantation

Author

Doisne, Jean-Marc, Hüber, Christian M, Okkenhaug, Klaus, Colucci, Francesco, Department of Obstetrics and Gynaecology [Cambridge, UK] (School of Clinical Medicine), University of Cambridge [UK] (CAM)-National Institute for Health Research [Cambridge, UK]-Cambridge Biomedical Research Centre [Cambridge, UK], Babraham Institute, Okkenhaug, Klaus [0000-0002-9432-4051], Colucci, Francesco [0000-0001-5193-6376], and Apollo - University of Cambridge Repository

Subjects
Transplantation, Biomedical, [SDV]Life Sciences [q-bio], Hematology, Stem Cell Research, Regenerative Medicine, Article, Rare Diseases, surgical procedures, operative, Basic Science, lcsh:Biology (General), 1107 Immunology, Stem Cell Research - Nonembryonic - Human, immune system diseases, Stem Cell Research - Nonembryonic - Non-Human, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Cancer
Abstract

Summary Allogeneic hematopoietic stem cell transplantation (HSCT) can treat certain hematologic malignancies due to the graft versus leukemia (GvL) effect but is complicated by graft versus host disease (GvHD). Expression of the p110δ catalytic subunit of the phosphoinositide 3-kinase pathway is restricted to leukocytes, where it regulates proliferation, migration, and cytokine production. Here, in a mouse model of fully mismatched hematopoietic cell transplantation (HCT), we show that genetic inactivation of p110δ in T cells leads to milder GvHD, whereas GvL is preserved. Inactivation of p110δ in human lymphocytes reduced T cell allorecognition. We demonstrate that both allostimulation and granzyme B expression were dependent on p110δ in naive T cells, which are the main mediators of GvHD, whereas memory T cells were unaffected. Strikingly, p110δ is not mandatory for either naive or memory T cells to mediate GvL. Therefore, immunomodulation of selective naive T cell functions by p110δ inactivation improves the outcome of allogeneic HSCT., Graphical Abstract, Highlights • Genetic p110δ inactivation in donor naive T cells mitigates GvHD in mice • Pharmacological p110δ inactivation in human T cells reduces alloreactivity, Using a mouse model of fully mismatched hematopoietic cell transplantation, Doisne et al. show that p110δ inactivation interferes with selective naive T cell functions and favorably sways the balance between graft versus leukemia and graft versus host disease. Furthermore, inactivation of p110δ in human lymphocytes reduces T cell allorecognition.

Published
2015

25. IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of mismatched hematopoietic cell transplantation

Author

Hüber, Christian, Doisne, Jean‐Marc, Colucci, Francesco, Colucci, Francesco [0000-0001-5193-6376], Apollo - University of Cambridge Repository, Doisne, Jean-Marc, Universität Salzburg, Department of Obstetrics and Gynaecology [Cambridge, UK] (School of Clinical Medicine), and University of Cambridge [UK] (CAM)-National Institute for Health Research [Cambridge, UK]-Cambridge Biomedical Research Centre [Cambridge, UK]

Subjects
Lymphoma, [SDV]Life Sciences [q-bio], Gene Expression, Graft vs Host Disease, Lymphocyte Activation, Immunotherapy, Adoptive, Interferon-gamma, Mice, Animals, Transplantation, Homologous, ComputingMilieux_MISCELLANEOUS, GvHD, Interleukin-15, Transplantation Chimera, Hematopoietic Stem Cell Transplantation, Interleukin-18, Cytokine-induced NK cells, Interleukin-12, [SDV] Life Sciences [q-bio], Killer Cells, Natural, Disease Models, Animal, Phenotype, HSCT, Cytokines, Female, T-Box Domain Proteins
Abstract

Mismatched hematopoietic cell transplants for treating leukemia are complicated by graft versus host disease (GvHD). Here, we show that adoptively transferred IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of fully mismatched hematopoietic cell transplantation. These IL-12/15/18-preactivated NK cells maintained Eomesodermin (Eomes) and T-bet expression upon transfer and, while there was no evidence of direct killing of donor T cells or host DCs by the IL-12/15/18-preactivated NK cells, proliferation of donor T cells was inhibited. Strikingly, the graft versus leukemia effect mediated by donor T cells was retained, resulting in improved overall survival of mice that received lymphoma cells, donor allogeneic T cells, and IL-12/15/18-preactivated NK cells. These results suggest that IL-12/15/18-preactivated NK cells may be useful in improving immunotherapy of mismatched hematopoietic cell transplantation. Compared with previously proposed protocols, our findings suggest that in vitro NK-cell preactivation with this cytokine cocktail offers the significant advantage that cytokines do not need to be administered systemically to sustain NK-cell activity, thus avoiding toxicity.

Published
2015

26. Molecular definition of group 1 innate lymphoid cells in the mouse uterus

Author

Filipovic, Iva, primary, Chiossone, Laura, additional, Vacca, Paola, additional, Hamilton, Russell S, additional, Ingegnere, Tiziano, additional, Doisne, Jean-Marc, additional, Hawkes, Delia A, additional, Mingari, Maria Cristina, additional, Sharkey, Andrew, additional, Moretta, Lorenzo, additional, and Colucci, Francesco, additional

Published
2018
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27. The Residual Innate Lymphoid Cells in NFIL3-Deficient Mice Support Suboptimal Maternal Adaptations to Pregnancy

Author

Boulenouar, Selma, primary, Doisne, Jean-Marc, additional, Sferruzzi-Perri, Amanda, additional, Gaynor, Louise M., additional, Kieckbusch, Jens, additional, Balmas, Elisa, additional, Yung, Hong Wa, additional, Javadzadeh, Shagayegh, additional, Volmer, Léa, additional, Hawkes, Delia A., additional, Phillips, Keli, additional, Brady, Hugh J.M., additional, Fowden, Abigail L., additional, Burton, Graham J., additional, Moffett, Ashley, additional, and Colucci, Francesco, additional

Published
2016
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28. Composition, Development, and Function of Uterine Innate Lymphoid Cells

Author

Doisne, Jean-Marc, primary, Balmas, Elisa, additional, Boulenouar, Selma, additional, Gaynor, Louise M., additional, Kieckbusch, Jens, additional, Gardner, Lucy, additional, Hawkes, Delia A., additional, Barbara, Cynthia F., additional, Sharkey, Andrew M., additional, Brady, Hugh J. M., additional, Brosens, Jan J., additional, Moffett, Ashley, additional, and Colucci, Francesco, additional

Published
2015
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30. Cutting Edge: Crucial Role of IL-1 and IL-23 in the Innate IL-17 Response of Peripheral Lymph Node NK1.1− Invariant NKT Cells to Bacteria

Author

Doisne, Jean-Marc, primary, Soulard, Valérie, additional, Bécourt, Chantal, additional, Amniai, Latiffa, additional, Henrot, Pauline, additional, Havenar-Daughton, Colin, additional, Blanchet, Charlène, additional, Zitvogel, Laurence, additional, Ryffel, Bernhard, additional, Cavaillon, Jean-Marc, additional, Marie, Julien C., additional, Couillin, Isabelle, additional, and Benlagha, Kamel, additional

Published
2011
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32. iNKT cell development is orchestrated by different branches of TGF-β signaling

Author

Doisne, Jean-Marc, primary, Bartholin, Laurent, additional, Yan, Kai-Ping, additional, Garcia, Céline N., additional, Duarte, Nadia, additional, Le Luduec, Jean-Benoît, additional, Vincent, David, additional, Cyprian, Farhan, additional, Horvat, Branka, additional, Martel, Sylvie, additional, Rimokh, Ruth, additional, Losson, Régine, additional, Benlagha, Kamel, additional, and Marie, Julien C., additional

Published
2009
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34. Coordinated Expression of Ig-Like Inhibitory MHC Class I Receptors and Acquisition of Cytotoxic Function in Human CD8+ T Cells

Author

Anfossi, Nicolas, primary, Doisne, Jean-Marc, additional, Peyrat, Marie-Alix, additional, Ugolini, Sophie, additional, Bonnaud, Olivia, additional, Bossy, David, additional, Pitard, Vincent, additional, Merville, Pierre, additional, Moreau, Jean-François, additional, Delfraissy, Jean-François, additional, Dechanet-Merville, Julie, additional, Bonneville, Marc, additional, Venet, Alain, additional, and Vivier, Eric, additional

Published
2004
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36. Cutting Edge: Crucial Role of IL-1 and IL-23 in the Innate IL-17 Response of Peripheral Lymph Node NK1.1- Invariant NKT Cells to Bacteria.

Author

Doisne, Jean-Marc, Soulard, Valerie, Becourt, Chantal, Amniai, Latiffa, Henrot, Pauline, Havenar-Daughton, Cohn, Blanchet, Charlëne., Zitvogel, Laurence, Ryffel, Bernhard, Cavai11on, Jean-Marc, Marie, Julien C, Couillin, Isabelle, and Benlagha, Kamel

Subjects
*LYMPH nodes, *DENDRITIC cells, *CYTOKINES, *BACTERIAL diseases, *CELLS
Abstract

We have shown previously that peripheral lymph node resident retinoic acid receptor-related orphan receptor γt+ NK1.1- invariant NKT (iNKT) cells produce IL- 17A independently of IL-6. In this study, we show that the concomitant presence of IL-i and IL-23 is crucial to induce a rapid and sustained IL-17A/F and IL-22 response by these cells that requires TCR-CD 1d in teraction and partly relies on IL-23-mediated upregulation of IL-23R and IL-1R1 expression. We further show that IL-i and IL-23 produced by pathogen-asso- ciated molecular pattern-stimulated dendritic cells in- duce this response from NK1.1 - iNKT cells in vitro, involving mainly TLR2/4-signaling pathways. Finally, we found that IL-17A production by these cells occurs very early and transiently in vivo in response to heat- killed bacteria. Overall, our study indicates that peripheral lymph node N K1.1 - iNKT cells could be a source of innate Th 17-related cytokines during bacterial infections and supports the hypothesis that they are able to provide an efficient first line of defense against bacterial invasion. [ABSTRACT FROM AUTHOR]

Published
2011
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37. Identification of a particular HIV-specific CD8+T-cell subset with a CD27+CD45RO−/RA+phenotype and memory characteristics after initiation of HAART during acute primary HIV infection

Author

Lécuroux, Camille, Girault, Isabelle, Urrutia, Alejandra, Doisne, Jean-Marc, Deveau, Christiane, Goujard, Cécile, Meyer, Laurence, Sinet, Martine, and Venet, Alain

Abstract

CD8+T cells play an important role in controlling viral infections. Defective CD8+T-cell responses during HIV infection could contribute to viral persistence. Early initiation of highly active antiretroviral therapy during acute primary HIV infection helps to preserve HIV-specific immune responses. Here, we describe a particular CD27+CD45RO−/RA+HIV-specific CD8+T cell in participants treated early during the primary infection. These cells, which were present at a very low frequency during primary HIV infection, increased markedly after early treatment, whereas their frequency remained unchanged in untreated participants and in participants treated later. These nonnaive antigen-experienced cells are in a resting state and have characteristics of long-lived memory cells. They also possess direct effector capabilities, such as cytokine production, and are able to proliferate and to acquire cytotoxic functions on reactivation. Our results suggest that these HIV-specific CD27+CD45RO−/RA+CD8+T cells, observed when early viral replication is inhibited, form a pool of resting cells with memory characteristics.

Published
2009
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38. Defects in mucosal immunity and nasopharyngeal dysbiosis in HSC-transplanted SCID patients with IL2RG/JAK3 deficiency

Author

Goncalves, Pedro, Doisne, Jean-Marc, Eri, Toshiki, Charbit, Bruno, Bondet, Vincent, Posseme, Celine, Llibre, Alba, The Milieu Interieur, Consortium, Casrouge, Armanda, Lenoir, Christelle, Neven, Bénédicte, Duffy, Darragh, Fischer, Alain, Di Santo, James, Institut Pasteur [Paris] (IP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This study was supported by grants from the Institut Pasteur, INSERM, ANR (15-CE15-000-ILC3_MEMORY) and ERC (695467-ILC_REACTIVITY). P. Gonçalves was supported in part by the Labex Milieu Intérieur (ANR 10-LBX-69 MI). The Biomics Platform is supported by France Génomique (ANR-10-INBS-09-09) and IBISA, We thank Sean Kennedy and Laurence Motreff (Biomics Platform) for 16S rRNA sequencing, Amine Ghozlane and Emna Achouri (HUB) for assistance with sequencing data analysis and the Di Santo laboratory for discussions., ANR-15-CE15-0004,ILC3_MEMORY,Les cellules lymphoïdes innées et la mémoire immunologique(2015), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), European Project: 695467,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ILC_REACTIVITY(2016), Di Santo, James, Les cellules lymphoïdes innées et la mémoire immunologique - - ILC3_MEMORY2015 - ANR-15-CE15-0004 - AAPG2015 - VALID, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, and Biological Determinants of ILC Reactivity for Immune Responses in Health and Disease - ILC_REACTIVITY - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-08-01 - 2021-07-31 - 695467 - VALID

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Janus Kinase 3, Cell Biology, Hematology, Biochemistry, Immunity, Innate, Immunoglobulin A, Dysbiosis, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Severe Combined Immunodeficiency, Lymphocytes, Immunity, Mucosal, Interleukin Receptor Common gamma Subunit
Abstract

Both innate and adaptive lymphocytes have critical roles in mucosal defense that contain commensal microbial communities and protect against pathogen invasion. Here we characterize mucosal immunity in patients with severe combined immunodeficiency (SCID) receiving hematopoietic stem cell transplantation (HSCT) with or without myeloablation. We confirmed that pretransplant conditioning had an impact on innate (natural killer and innate lymphoid cells) and adaptive (B and T cells) lymphocyte reconstitution in these patients with SCID and now show that this further extends to generation of T helper 2 and type 2 cytotoxic T cells. Using an integrated approach to assess nasopharyngeal immunity, we identified a local mucosal defect in type 2 cytokines, mucus production, and a selective local immunoglobulin A (IgA) deficiency in HSCT-treated SCID patients with genetic defects in IL2RG/GC or JAK3. These patients have a reduction in IgA-coated nasopharyngeal bacteria and exhibit microbial dysbiosis with increased pathobiont carriage. Interestingly, intravenous immunoglobulin replacement therapy can partially normalize nasopharyngeal immunoglobulin profiles and restore microbial communities in GC/JAK3 patients. Together, our results suggest a potential nonredundant role for type 2 immunity and/or of local IgA antibody production in the maintenance of nasopharyngeal microbial homeostasis and mucosal barrier function.

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39. IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of mismatched hematopoietic cell transplantation

Author

Hüber, Christian M, Doisne, Jean-Marc, and Colucci, Francesco

Subjects
Cytokine-induced NK cells, GvHD, Interleukin-15, Transplantation Chimera, Lymphoma, Hematopoietic Stem Cell Transplantation, Interleukin-18, Gene Expression, Graft vs Host Disease, Lymphocyte Activation, Immunotherapy, Adoptive, Interleukin-12, 3. Good health, Killer Cells, Natural, Disease Models, Animal, Interferon-gamma, Mice, Phenotype, HSCT, Animals, Cytokines, Transplantation, Homologous, Female, T-Box Domain Proteins
Abstract

Mismatched hematopoietic cell transplants for treating leukemia are complicated by graft versus host disease (GvHD). Here, we show that adoptively transferred IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of fully mismatched hematopoietic cell transplantation. These IL-12/15/18-preactivated NK cells maintained Eomesodermin (Eomes) and T-bet expression upon transfer and, while there was no evidence of direct killing of donor T cells or host DCs by the IL-12/15/18-preactivated NK cells, proliferation of donor T cells was inhibited. Strikingly, the graft versus leukemia effect mediated by donor T cells was retained, resulting in improved overall survival of mice that received lymphoma cells, donor allogeneic T cells, and IL-12/15/18-preactivated NK cells. These results suggest that IL-12/15/18-preactivated NK cells may be useful in improving immunotherapy of mismatched hematopoietic cell transplantation. Compared with previously proposed protocols, our findings suggest that in vitro NK-cell preactivation with this cytokine cocktail offers the significant advantage that cytokines do not need to be administered systemically to sustain NK-cell activity, thus avoiding toxicity.

40. CXCR3 and CXCR5 are highly expressed in HIV‐1‐specific CD8 central memory T cells from infected patients

Author

Benoit Favier, Laurence Meyer, Anaelle Olivo, Géraldine Schlecht-Louf, Marie Bitu, Camille Lécuroux, Véronique Avettand-Fenoel, Faroudy Boufassa, Christine Bourgeois, Cécile Goujard, Bruno Vaslin, Asma Essat, Nicolas Noel, Olivier Lambotte, Jean-Marc Doisne, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Laboratoire de Microbiologie Clinique [AP-HP Hôpital Necker-Enfants Malades], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inflammation, microbiome, immunosurveillance (MI2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de Médecine Interne - Immunologie Clinique [AP-HP Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Agence Nationale de Recherches sur le Sida et les Hépatites Virales. Grant Number: ECTZ117636, Doisne, Jean-Marc, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Paris (UP), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, Receptors, CXCR5, 0301 basic medicine, Senescence, Receptors, CXCR3, Chemokine receptor, [SDV]Life Sciences [q-bio], Immunology, HIV Infections, Migratory profile, CD8-Positive T-Lymphocytes, Biology, CXCR3, CXCR5, 03 medical and health sciences, 0302 clinical medicine, T-Lymphocyte Subsets, CX3CR1, medicine, Humans, Immunology and Allergy, Cytotoxic T cell, HIV controller, Middle Aged, HIV infection, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, HIV-1, Female, Immunologic Memory, Memory T cell, CD8, 030215 immunology, CD8 T cell
Abstract

International audience; New ways of characterizing CD8+ memory T cell responses in chronic infections are based on the measurement of chemokine receptor expression (CXCR3, CXCR5, and CX3CR1). We applied these novel phenotyping strategies to chronic HIV infection by comparing healthy donors (HDs), HIV-infected patients receiving antiretroviral therapy (ART), and spontaneous HIV controllers (HICs). In all groups, the memory cells exhibited high proportion of CXCR3+ cells. Proportions of CXCR5+ and CX3CR1+ cells were preferentially observed among central memory cells (Tcm) and effector memory cells (Tem) respectively. Chronic controlled HIV infection impacted the chemokine receptor profile of both HIV-specific and nonspecific CD8+ T cells. In total CD8+ T cells, the proportions of CXCR3- CXCR5- CX3CR1- Tcm and Tem were lower in HIV-infected patients than in HDs with subtle differences between ART and HICs. Such phenotyping strategy also revealed differences in exhaustion and senescence phenotypes, the CXCR3+ CXCR5+ CX3CR1- being more exhausted and senescent than the CXCR3+ CXCR5- CX3CR1- Tcm fraction. Among HIV-specific CD8+ T cells, the vast majority of Tcm cells were CXCR3+ and CXCR5+ cells in contrast with their nonspecific counterparts. In conclusion, the addition of migration markers contributes to better characterize Tcm/Tem compartment.

Published
2021

41. IL-7-dependent and -independent lineages of IL-7R-dependent human T cells.

Author

Arango-Franco CA, Ogishi M, Unger S, Delmonte OM, Orrego JC, Yatim A, Velasquez-Lopera MM, Zea-Vera AF, Bohlen J, Chbihi M, Fayand A, Sánchez JP, Rojas J, Seeleuthner Y, Le Voyer T, Philippot Q, Payne KJ, Gervais A, Erazo-Borrás LV, Correa-Londoño LA, Cederholm A, Gallón-Duque A, Goncalves P, Doisne JM, Horev L, Charmeteau-de Muylder B, Álvarez JÁ, Arboleda DM, Pérez-Zapata L, Vásquez-Echeverri E, Moncada-Vélez M, López JA, Caicedo Y, Palterer B, Patiño PJ, Montoya CJ, Chaldebas M, Zhang P, Nguyen T, Ma CS, Jeljeli M, Alzate JF, Cabarcas F, Khan T, Rinchai D, Prétet JL, Boisson B, Marr N, Ibrahim R, Molho-Pessach V, Boisson-Dupuis S, Kiritsi D, Barata JT, Landegren N, Neven B, Abel L, Lisco A, Béziat V, Jouanguy E, Bustamante J, Di Santo JP, Tangye SG, Notarangelo LD, Cheynier R, Natsuga K, Arias AA, Franco JL, Warnatz K, Casanova JL, and Puel A

Subjects
Humans, Adult, Male, Female, Middle Aged, Severe Combined Immunodeficiency immunology, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency pathology, Cell Lineage immunology, T-Lymphocytes immunology, Interleukin-7 Receptor alpha Subunit, Interleukin-7 immunology, Interleukin-7 genetics, Interleukin-7 metabolism, Receptors, Interleukin-7 genetics, Receptors, Interleukin-7 immunology, Receptors, Interleukin-7 metabolism
Abstract

Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T-B+NK+ SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive CD4+ T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory CD4+ and CD8+ T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including TCRγδ+ T cells and some TCRαβ+ T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral CD4+ T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development.

Published
2024
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42. A human immune system (HIS) mouse model that dissociates roles for mouse and human FcR + cells during antibody-mediated immune responses.

Author

Thaller AL, Jönsson F, Fiquet O, Marie S, Doisne JM, Girelli-Zubani G, Eri T, Fernandes P, Tatirovsky E, Langa-Vives F, Bruhns P, Strick-Marchand H, and Di Santo JP

Subjects
Humans, Mice, Animals, Immunoglobulin G, Antibody-Dependent Cell Cytotoxicity, Macrophages, Complement System Proteins, Adaptive Immunity, Receptors, Fc, Receptors, IgG genetics
Abstract

Human immune system (HIS) mice provide a model to study human immune responses in vivo. Currently available HIS mouse models may harbor mouse Fc Receptor (FcR)-expressing cells that exert potent effector functions following administration of human Ig. Previous studies showed that the ablation of the murine FcR gamma chain (FcR-γ) results in loss of antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vivo. We created a new FcR-γ-deficient HIS mouse model to compare host (mouse) versus graft (human) effects underlying antibody-mediated immune responses in vivo. FcR-γ-deficient HIS recipients lack expression and function of mouse activating FcRs and can be stably and robustly reconstituted with human immune cells. By screening blood B-cell depletion by rituximab Ig variants, we found that human FcγRs-mediated IgG1 effects, whereas mouse activating FcγRs were dominant in IgG4 effects. Complement played a role as an IgG1 variant (IgG1 K322A) lacking complement binding activity was largely ineffective. Finally, we provide evidence that FcγRIIIA on human NK cells could mediate complement-independent B-cell depletion by IgG1 K322A. We anticipate that our FcR-γ-deficient HIS model will help clarify mechanisms of action of exogenous administered human antibodies in vivo., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Published
2023
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43. STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice.

Author

Bennion BG, Croft CA, Ai TL, Qian W, Menos AM, Miner CA, Frémond ML, Doisne JM, Andhey PS, Platt DJ, Bando JK, Wang ER, Luksch H, Molina TJ, Roberson EDO, Artyomov MN, Rösen-Wolff A, Colonna M, Rieux-Laucat F, Di Santo JP, Neven B, and Miner JJ

Subjects
Animals, Gain of Function Mutation immunology, Lymphoid Tissue immunology, Mice, Organogenesis immunology, Cell Differentiation immunology, Immunity, Innate immunology, Lymph Nodes immunology, Lymphocytes cytology, T-Lymphocytes, Helper-Inducer immunology
Abstract

STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer's patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4β7 + progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in RORγT-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. RORγT lineage-specific expression of STING gain-of-function also causes lung disease. Since RORγT is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2020
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44. IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of mismatched hematopoietic cell transplantation.

Author

Hüber CM, Doisne JM, and Colucci F

Subjects
Animals, Cytokines pharmacology, Disease Models, Animal, Female, Gene Expression, Graft vs Host Disease therapy, Interferon-gamma biosynthesis, Interleukin-12 pharmacology, Interleukin-15 pharmacology, Interleukin-18 pharmacology, Killer Cells, Natural drug effects, Killer Cells, Natural metabolism, Lymphocyte Activation drug effects, Mice, Phenotype, T-Box Domain Proteins genetics, T-Box Domain Proteins metabolism, Transplantation Chimera, Transplantation, Homologous, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation adverse effects, Immunotherapy, Adoptive, Killer Cells, Natural immunology, Lymphocyte Activation immunology
Abstract

Mismatched hematopoietic cell transplants for treating leukemia are complicated by graft versus host disease (GvHD). Here, we show that adoptively transferred IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of fully mismatched hematopoietic cell transplantation. These IL-12/15/18-preactivated NK cells maintained Eomesodermin (Eomes) and T-bet expression upon transfer and, while there was no evidence of direct killing of donor T cells or host DCs by the IL-12/15/18-preactivated NK cells, proliferation of donor T cells was inhibited. Strikingly, the graft versus leukemia effect mediated by donor T cells was retained, resulting in improved overall survival of mice that received lymphoma cells, donor allogeneic T cells, and IL-12/15/18-preactivated NK cells. These results suggest that IL-12/15/18-preactivated NK cells may be useful in improving immunotherapy of mismatched hematopoietic cell transplantation. Compared with previously proposed protocols, our findings suggest that in vitro NK-cell preactivation with this cytokine cocktail offers the significant advantage that cytokines do not need to be administered systemically to sustain NK-cell activity, thus avoiding toxicity., (© 2015 The Authors. European Journal of Immunology published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2015
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45. Skin and peripheral lymph node invariant NKT cells are mainly retinoic acid receptor-related orphan receptor (gamma)t+ and respond preferentially under inflammatory conditions.

Author

Doisne JM, Becourt C, Amniai L, Duarte N, Le Luduec JB, Eberl G, and Benlagha K

Subjects
Animals, Cell Proliferation drug effects, Epithelial Cells pathology, Galactosylceramides pharmacology, Inflammation pathology, Interleukin-17, Interleukin-6 deficiency, Lymph Nodes pathology, Mice, Mice, Knockout, Natural Killer T-Cells immunology, Nuclear Receptor Subfamily 1, Group F, Member 3, Skin pathology, Inflammation immunology, Lymph Nodes cytology, Natural Killer T-Cells cytology, Receptors, Retinoic Acid, Receptors, Thyroid Hormone, Skin cytology
Abstract

Lymph nodes (LNs) have been long considered as comprising few invariant NKT (iNKT) cells, and these cells have not been studied extensively. In this study, we unravel the existence of stable rather than transitional LN-resident NK1.1(-) iNKT cell populations. We found the one resident in peripheral LNs (PLNs) to comprise a major IL-17-producing population and to express the retinoic acid receptor-related orphan receptor (gamma)t (ROR(gamma)t). These cells respond to their ligand alpha-galactosylceramide (alpha-GalCer) in vivo by expanding dramatically in the presence of LPS, providing insight into how this rare population could have an impact in immune responses to infection. PLN-resident ROR(gamma)t(+) NK1.1(-) iNKT cells express concomitantly CCR6, the integrin alpha-chain alpha(E) (CD103), and IL-1R type I (CD121a), indicating that they might play a role in inflamed epithelia. Accordingly, skin epithelia comprise a major ROR(gamma)t(+) CCR6(+)CD103(+)CD121a(+) NK1.1(-) cell population, reflecting iNKT cell composition in PLNs. Importantly, both skin and draining PLN ROR(gamma)t(+) iNKT cells respond preferentially to inflammatory signals and independently of IL-6, indicating that they could play a nonredundant role during inflammation. Overall, our study indicates that ROR(gamma)t(+) iNKT cells could play a major role in the skin during immune responses to infection and autoimmunity.

Published
2009
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46. iNKT cell development is orchestrated by different branches of TGF-beta signaling.

Author

Doisne JM, Bartholin L, Yan KP, Garcia CN, Duarte N, Le Luduec JB, Vincent D, Cyprian F, Horvat B, Martel S, Rimokh R, Losson R, Benlagha K, and Marie JC

Subjects
Animals, Apoptosis physiology, Cell Lineage, Interleukin-2 Receptor beta Subunit immunology, Mice, Mice, Transgenic, Natural Killer T-Cells cytology, Receptors, Transforming Growth Factor beta genetics, Receptors, Transforming Growth Factor beta immunology, Smad4 Protein genetics, Smad4 Protein immunology, Spleen cytology, Stem Cells cytology, Stem Cells physiology, T-Box Domain Proteins immunology, T-Lymphocyte Subsets cytology, Transcription Factors genetics, Transcription Factors immunology, Transforming Growth Factor beta genetics, Cell Differentiation immunology, Natural Killer T-Cells physiology, Signal Transduction physiology, T-Lymphocyte Subsets physiology, Transforming Growth Factor beta immunology
Abstract

Invariant natural killer T (iNKT) cells constitute a distinct subset of T lymphocytes exhibiting important immune-regulatory functions. Although various steps of their differentiation have been well characterized, the factors controlling their development remain poorly documented. Here, we show that TGF-beta controls the differentiation program of iNKT cells. We demonstrate that TGF-beta signaling carefully and specifically orchestrates several steps of iNKT cell development. In vivo, this multifaceted role of TGF-beta involves the concerted action of different pathways of TGF-beta signaling. Whereas the Tif-1gamma branch controls lineage expansion, the Smad4 branch maintains the maturation stage that is initially repressed by a Tif-1gamma/Smad4-independent branch. Thus, these three different branches of TGF-beta signaling function in concert as complementary effectors, allowing TGF-beta to fine tune the iNKT cell differentiation program.

Published
2009
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