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1. Dichotomous metabolic networks govern human ILC2 proliferation and function

Author

Carys A. Croft, James P. Di Santo, Antonia Cama, Solenne Marie, Carmen Buchrieser, Davide Topazio, Olimpia Musumeci, Valerie Dardalhon, Laura Surace, Naomi Taylor, Jean-Marc Doisne, Vincent Guillemot, Natalia Petrosemoli, Pedro Escoll, Ido Amit, Anna Thaller, Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Biologie des Bactéries intracellulaires - Biology of Intracellular Bacteria, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Department of Otolaryngology, Ospedale 'Giuseppe Mazzini' di Teramo, Department of Maxillofacial and Otolaryngology, Hospital 'Floraspe Renzetti', Department of Immunology [Rehovot, Israël], Weizmann Institute of Science [Rehovot, Israël], Department of Clinical and Experimental Medicine [Messina, Italy], University of Messina, The Innate Immunity Unit is supported by grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur, the Agence National pour le Recherche (ANR) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (695467, ILC_REACTIVITY). A.T. is supported by European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 765104. C.B.’s group was supported by the Fondation pour la Recherche Médicale (FRM) grant no. EQU201903007847 and the grant no. ANR-10-LABX-62-IBEID. L.S. was supported by an SNSF-Early PostDoc. Mobility fellowship and a Marie Curie grant (H2020- MSCA-IF-2017)., We thank all the members of the Innate Immunity Unit for helpful discussions, the Centre de Recherche Translationnelle and the logistic department of Institut Pasteur. We thank the CB-UTechS platform for cytometry support and the Imagopole-CiTech (part of France-BioImaging supported by ANR grant no. ANR-10-INSB-04-01, Conseil de la Region Ile-de-France, FRM) for technical support., The study was conceptualized by L.S. and J.P.D. Experiments were coordinated by L.S. FACS and subsequent analyses were performed by L.S., C.A.C., A.T., J.-M.D. and S.M. Confocal microscopy analysis was performed by P.E., C.B. and L.S. Bioinformatic analyses were performed by N.P. and V.G. RNA-seq experiments were conducted by I.A. O.M., V.D., N.T., D.T. and A.C. provided resources. L.S. and J.P.D. wrote the paper. Funding was acquired by L.S. and J.P.D., and the study was supervised by J.P.D., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 695467,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ILC_REACTIVITY(2016), European Project: 765104,MATURE-NK, European Project: 796004,BIF-SCV, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED BioSPC), Université Sorbonne Paris Cité (USPC)-Université de Paris (UP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Hospital 'Giuseppe Mazzini'

Subjects
Letter, Mitochondrial Diseases, Lymphocyte Activation, 0302 clinical medicine, Immunology and Allergy, Glycolysis, Receptor, Tissue homeostasis, Cells, Cultured, 0303 health sciences, MESH: Cytokines, Innate lymphoid cell, MESH: Energy Metabolism, MESH: Arginine, MESH: Mitochondrial Diseases, MESH: Case-Control Studies, Cell biology, Mitochondria, Phenotype, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, MESH: Immunity, Innate, MESH: Cells, Cultured, MESH: Interleukin-33, MESH: Mitochondria, Immunology, Innate lymphoid cells, Oxidative phosphorylation, Biology, MESH: Phenotype, Arginine, 03 medical and health sciences, Th2 Cells, MESH: Th2 Cells, MESH: Cell Proliferation, Humans, MESH: Lymphocyte Activation, PI3K/AKT/mTOR pathway, 030304 developmental biology, Cell Proliferation, MESH: Humans, Interleukins, Metabolism, Interleukin-33, Immunity, Innate, Metabolic pathway, Case-Control Studies, Energy Metabolism, Amino Acids, Branched-Chain, 030215 immunology, MESH: Amino Acids, Branched-Chain
Abstract

Group 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (TH2) that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited, and its key regulators are unknown. Here, we show that circulating ‘naive’ ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (mTOR) to produce IL-13 while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2s, offering new strategies to target ILC2s in disease settings., ILC2 metabolism has been largely unexplored. Di Santo and colleagues examine metabolic profiles from naive and cytokine-activated ILC2s and find that IL-33-triggered ILC2s rely on distinct metabolic pathways to sustain proliferation and function.

Published
2021
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2. The Citrobacter rodentium type III secretion system effector EspO affects mucosal damage repair and antimicrobial responses

Author

James C. Wright, Nicolas Serafini, Gad Frankel, Eran Elinav, James P. Di Santo, Meirav Pevsner-Fischer, Cedric N. Berger, Valerie F. Crepin, Theodoros I. Roumeliotis, Jyoti S. Choudhary, Lu Yu, Medical Research Council Centre for Molecular Bacteriology and Infection [Londres, Royaume-Uni] (MRC CMBI), Imperial College London, Division of Cancer Biology [Londres, Royaume-Uni], The institute of cancer research [London], Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology [Rehovot, Israël], Weizmann Institute of Science [Rehovot, Israël], This project was supported by grant MR/K019007/1 awarded by the medical research council UK (https://mrc.ukri.org), by grants WT098051 and 107057/Z/15/Z awarded by the Wellcome Trust (https://wellcome.ac.uk/) and by grant 695467 – ILC_REACTIVITY awarded by the European Research Council (https://erc.europa.eu)., European Project: 695467,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ILC_REACTIVITY(2016), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Bodescot, Myriam, 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
0301 basic medicine, Pulmonology, Neutrophils, Physiology, Secretion Systems, Pathology and Laboratory Medicine, Biochemistry, Type three secretion system, Mice, White Blood Cells, Intestinal mucosa, Animal Cells, Microbial Physiology, Citrobacter rodentium, Type III Secretion Systems, Medicine and Health Sciences, Bacterial Physiology, Biology (General), Intestinal Mucosa, Post-Translational Modification, Phosphorylation, Immune Response, Effector, Innate lymphoid cell, Enterobacteriaceae Infections, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Cell Processes, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Anatomy, Cellular Types, Pathogens, Research Article, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, Colon, Virulence Factors, Immune Cells, 030106 microbiology, Immunology, Biology, digestive system, Microbiology, 03 medical and health sciences, Immune system, Virology, Tissue Repair, Genetics, Animals, Secretion, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Biology, Cell Proliferation, Innate immune system, Blood Cells, Biology and Life Sciences, Proteins, Bacteriology, Cell Biology, RC581-607, Immunity, Innate, Mice, Inbred C57BL, Gastrointestinal Tract, 030104 developmental biology, Respiratory Infections, Parasitology, Immunologic diseases. Allergy, Physiological Processes, Digestive System, Antimicrobial Cationic Peptides
Abstract

Infection with Citrobacter rodentium triggers robust tissue damage repair responses, manifested by secretion of IL-22, in the absence of which mice succumbed to the infection. Of the main hallmarks of C. rodentium infection are colonic crypt hyperplasia (CCH) and dysbiosis. In order to colonize the host and compete with the gut microbiota, C. rodentium employs a type III secretion system (T3SS) that injects effectors into colonic intestinal epithelial cells (IECs). Once injected, the effectors subvert processes involved in innate immune responses, cellular metabolism and oxygenation of the mucosa. Importantly, the identity of the effector/s triggering the tissue repair response is/are unknown. Here we report that the effector EspO ,an orthologue of OspE found in Shigella spp, affects proliferation of IECs 8 and 14 days post C. rodentium infection as well as secretion of IL-22 from colonic explants. While we observed no differences in the recruitment of group 3 innate lymphoid cells (ILC3s) and T cells, which are the main sources of IL-22 at the early and late stages of C. rodentium infection respectively, infection with ΔespO was characterized by diminished recruitment of sub-mucosal neutrophils, which coincided with lower abundance of Mmp9 and chemokines (e.g. S100a8/9) in IECs. Moreover, mice infected with ΔespO triggered significantly lesser nutritional immunity (e.g. calprotectin, Lcn2) and expression of antimicrobial peptides (Reg3β, Reg3γ) compared to mice infected with WT C. rodentium. This overlapped with a decrease in STAT3 phosphorylation in IECs. Importantly, while the reduced CCH and abundance of antimicrobial proteins during ΔespO infection did not affect C. rodentium colonization or the composition of commensal Proteobacteria, they had a subtle consequence on Firmicutes subpopulations. EspO is the first bacterial virulence factor that affects neutrophil recruitment and secretion of IL-22, as well as expression of antimicrobial and nutritional immunity proteins in IECs., Author summary Citrobacter rodentium is a gold standard model to study pathogen-host-microbiome interactions. Two of the hallmarks of C. rodentium infection are colonic damage repair responses and colitis; symptoms that are shared with inflammatory bowel diseases in humans. The processes leading to tissue damage repair responses and the implicated bacterial virulence factors are still elusive. In this paper, we show that the C. rodentium type III secretion system effector EspO plays a major role in triggering damage healing responses, recruitment of neutrophils to the colonic villi, secretion of IL-22 from colonic explants and expression of IL-22 regulated genes in intestinal epithelial cells. This paper is the first to report a bacterial virulence factor that impacts on both intestinal epithelial cell proliferation and immune responses.

Published
2018

3. Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells

Author

Shalev Itzkovitz, François Gerbe, Anna Chuprin, Valérie S. Zimmermann, Chamutal Bornstein, Alice Machado, Shir Nevo, Marie Pouzolles, Philippe Jay, Jakub Abramson, Ori Goldberg, Noam Kadouri, Amir Giladi, Eyal David, Naomi Taylor, Ido Amit, Beáta Tóth, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Weizmann Institute of Science [Rehovot, Israël], Unité des Mycobactéries [Antananarivo, Madagascar] (IPM), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), and Department of Immunology [Rehovot, Israël]

Subjects
0301 basic medicine, Male, Models, Molecular, MESH: Interleukin-17, [SDV]Life Sciences [q-bio], Epigenesis, Genetic, Transcriptome, Mice, 0302 clinical medicine, MESH: Animals, MESH: Epigenesis, Genetic, education.field_of_study, Mice, Inbred BALB C, Multidisciplinary, Innate lymphoid cell, Interleukin-17, MESH: Transcription Factors, Cell biology, Chromatin, medicine.anatomical_structure, MESH: Epithelial Cells, Female, Central tolerance, Single-Cell Analysis, MESH: Models, Molecular, Cell type, Stromal cell, MESH: Interleukins, T cell, Population, MESH: Mice, Inbred BALB C, Thymus Gland, Biology, 03 medical and health sciences, MESH: Mice, Inbred C57BL, medicine, Animals, Humans, education, MESH: Mice, MESH: Humans, Interleukins, Epithelial Cells, MESH: Thymus Gland, MESH: Male, Mice, Inbred C57BL, 030104 developmental biology, MESH: Female, 030215 immunology, MESH: Single-Cell Analysis, Transcription Factors
Abstract

International audience; T cell development and selection are coordinated in the thymus by a specialized niche of diverse stromal populations1-3. Although much progress has been made over the years in identifying the functions of the different cell types of the thymic stromal compartment, there is no comprehensive characterization of their diversity and heterogeneity. Here we combined massively parallel single-cell RNA-sequencing4,5, spatial mapping, chromatin profiling and gene targeting to characterize de novo the entire stromal compartment of the mouse thymus. We identified dozens of cell states, with thymic epithelial cells (TECs) showing the highest degree of heterogeneity. Our analysis highlights four major medullary TEC (mTEC I-IV) populations, with distinct molecular functions, epigenetic landscapes and lineage regulators. Specifically, mTEC IV constitutes a new and highly divergent TEC lineage with molecular characteristics of the gut chemosensory epithelial tuft cells. Mice deficient in Pou2f3, a master regulator of tuft cells, have complete and specific depletion of mTEC IV cells, which results in increased levels of thymus-resident type-2 innate lymphoid cells. Overall, our study provides a comprehensive characterization of the thymic stroma and identifies a new tuft-like TEC population, which is critical for shaping the immune niche in the thymus.

Published
2017

4. Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells

Author

Clotilde Guyon, Erez Y. Levanon, Matthieu Giraud, Miri Danan-Gotthold, Jakub Abramson, The Mina & Everard Goodman Faculty of Life Sciences [Ramat Gan, Israël], Université Bar-Ilan [Israel], [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -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 Immunology [Rehovot, Israël], Weizmann Institute of Science, This work was supported by EYL: The European Research Council (grant no. 311257), the I-CORE Program of the Planning and Budgeting Committee in Israel (grant nos. 41/11 and 1796/12), and the Israel Science Foundation (1380/14).JA: Israel Science Foundation (1825/10), Sy Syms Foundation, Dr. Celia Zwillenberg-Fridman and Dr. Lutz Fridman Career Development Chair.MGi: The Agence Nationale de Recherche (2011-CHEX-001-R12004KK).MDG is grateful to the Azrieli Foundation for the award of an Azrieli Fellowship., Bos, Mireille, Bar-Ilan University [Israël], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Weizmann Institute of Science [Rehovot, Israël]

Subjects
0301 basic medicine, Cell type, RNA editing, [SDV]Life Sciences [q-bio], T-Lymphocytes, Thymus Gland, Biology, Self-tolerance, Autoantigens, 03 medical and health sciences, Mice, Immune system, Antigen, Gene expression, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV ] Life Sciences [q-bio], Research, Alternative splicing, RNA sequencing, Cell Differentiation, Epithelial Cells, Molecular biology, Cell biology, Thymus, Alternative Splicing, 030104 developmental biology, Self Tolerance, Medullary thymic epithelial cells (mTECs), Gene Expression Regulation, RNA splicing, Transcription Factors
Abstract

Background In order to become functionally competent but harmless mediators of the immune system, T cells undergo a strict educational program in the thymus, where they learn to discriminate between self and non-self. This educational program is, to a large extent, mediated by medullary thymic epithelial cells that have a unique capacity to express, and subsequently present, a large fraction of body antigens. While the scope of promiscuously expressed genes by medullary thymic epithelial cells is well-established, relatively little is known about the expression of variants that are generated by co-transcriptional and post-transcriptional processes. Results Our study reveals that in comparison to other cell types, medullary thymic epithelial cells display significantly higher levels of alternative splicing, as well as A-to-I and C-to-U RNA editing, which thereby further expand the diversity of their self-antigen repertoire. Interestingly, Aire, the key mediator of promiscuous gene expression in these cells, plays a limited role in the regulation of these transcriptional processes. Conclusions Our results highlight RNA processing as another layer by which the immune system assures a comprehensive self-representation in the thymus which is required for the establishment of self-tolerance and prevention of autoimmunity. Electronic supplementary material The online version of this article (doi:10.1186/s13059-016-1079-9) contains supplementary material, which is available to authorized users.

Published
2016

5. Examination of HER3 targeting in cancer using monoclonal antibodies

Author

Moshit Lindzen, Christel Larbouret, Myriam Chentouf, Manjusha Ghosh, Lucile Mounier, Yosef Yarden, Sai Dunoyer, Sara Lavi, Ali Abdul-Hai, Thierry Chardès, André Pèlegrin, Michael Sela, Hervé Bazin, Nadège Gaborit, Orith Leitner, Maicol Mancini, Department of Biological Regulation [Rehovot, Israel], Weizmann Institute of Science [Rehovot, Israël], Department of Internal Medicine [Rehovot, Israel], Kaplan Medical Center [Rehovot, Israel], Department of Biological Services [Rehovot, Israel], Cisbio Bioassays [Codolet, France] (Innovation Management / CbB), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Immunology [Rehovot, Israël], Our laboratories are supported by the Israel Cancer Research Fund, the M. D. Moross Cancer Research Institute, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation., 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), and KARLI, Mélanie

Subjects
Receptor, ErbB-3, medicine.drug_class, antibody combination, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pharmacology, Monoclonal antibody, Receptor tyrosine kinase, 03 medical and health sciences, 0302 clinical medicine, Drug Delivery Systems, [SDV.CAN] Life Sciences [q-bio]/Cancer, HER3, Pancreatic cancer, Cell Line, Tumor, medicine, Humans, Kinase activity, Autocrine signalling, skin and connective tissue diseases, 030304 developmental biology, 0303 health sciences, Multidisciplinary, biology, Cancer, Antibodies, Monoclonal, tyrosine kinase, Biological Sciences, medicine.disease, 3. Good health, body regions, 030220 oncology & carcinogenesis, biology.protein, cancer therapy, Antibody, Tyrosine kinase, signal transduction
Abstract

International audience; The human EGF receptor (HER/EGFR) family of receptor tyrosine kinases serves as a key target for cancer therapy. Specifically, EGFR and HER2 have been repeatedly targeted because of their genetic aberrations in tumors. The therapeutic potential of targeting HER3 has long been underestimated, due to relatively low expression in tumors and impaired kinase activity. Nevertheless, in addition to serving as a dimerization partner of EGFR and HER2, HER3 acts as a key player in tumor cells' ability to acquire resistance to cancer drugs. In this study, we generated several monoclonal antibodies to HER3. Comparisons of their ability to degrade HER3, decrease downstream signaling, and inhibit growth of cultured cells, as well as recruit immune effector cells, selected an antibody that later emerged as the most potent inhibitor of pancreatic cancer cells grown as tumors in animals. Our data predict that anti-HER3 antibodies able to intercept autocrine and stroma-tumor interactions might strongly inhibit tumor growth, in analogy to the mechanism of action of anti-EGFR antibodies routinely used now to treat colorectal cancer patients.

Published
2015

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