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1. High-affinity autoreactive plasma cells disseminate through multiple organs in patients with immune thrombocytopenic purpura

Author

Pablo Canales-Herrerias, Etienne Crickx, Matteo Broketa, Aurélien Sokal, Guilhem Chenon, Imane Azzaoui, Alexis Vandenberghe, Angga Perima, Bruno Iannascoli, Odile Richard-Le Goff, Carlos Castrillon, Guillaume Mottet, Delphine Sterlin, Ailsa Robbins, Marc Michel, Patrick England, Gael A. Millot, Klaus Eyer, Jean Baudry, Matthieu Mahevas, Pierre Bruhns, RICHARD-LE GOFF, ODILE, APPEL À PROJETS GÉNÉRIQUE 2018 - Etude de la rupture de tolérance dans une maladie humaine autoimmune médiée par les lymphocytes B - - Autoimmuni-B2018 - ANR-18-CE15-0001 - AAPG2018 - VALID, Appel à projets générique - Analyse en profondeur de répertoires d'anticorps par microfluidique en gouttelettes couplé à du séquençage haut-débit pour le diagnostic et la découverte d'anticorps thérapeutiques - - DROP-mAbs2014 - ANR-14-CE16-0011 - Appel à projets générique - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Equipements d'excellence - Institut Pierre Gilles de Gennes pour la microfluidique - - IPGG2010 - ANR-10-EQPX-0034 - EQPX - VALID, Laboratoire Colloïdes et Matériaux Divisés (LCMD), Chimie-Biologie-Innovation (UMR 8231) (CBI), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ecole Doctorale Frontières du Vivant - Programme Bettencourt (FdV), Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de référence maladie rare des cytopénies auto-immunes de l'adulte (GECAI - Hôpital Henri-Mondor - UPEC), Diaccurate SAS, Physiologie, physiopathologie et thérapeutique (ED 394), Sorbonne Université (SU), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Henri Mondor, Biophysique Moléculaire (plateforme) - Molecular Biophysics (platform), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), P.C-H. was supported partly by a stipend from the Pasteur - Paris University (PPU) InternationalPhD program, and by a fellowship from the French Fondation pour la Recherche Médicale (FRM). M.B.is the recipient of a CIFRE PhD fellowship. C.C. was supported by CONCYTEC, Peru. P.B. acknowledgesfunding from the French National Research Agency grants ANR-18-CE15-0001 project Autoimmuni-Band ANR-14-CE16-0011 project DROPmAbs, funding by the Institut Carnot Pasteur Microbes et Santé,the Institut Pasteur and the Institut National de la Santé et de la Recherche Médicale (INSERM). E.K.acknowledges funding from the Branco Weiss Fellowship (Society in Science) and the European ResearchCouncil (ERC) (grant agreement #80336). J.B. acknowledges funding from the French government throughBPIFrance under the frame 'Programme d’Investissements d’Avenir' (CELLIGO Project), the 'InstitutPierre-Gilles de Gennes' through the laboratoire d’excellence, 'Investissements d’avenir' programs ANR-10-IDEX-0001-02 PSL, ANR-10- EQPX-34 and ANR-10-LABX-3, The authors acknowledge Ms Laetitia Languille for the coordination of patient recruitment at Hôpital Henri Mondor, Créteil, France, Dr Maxime Moulard (BioCytex, Marseille, France) and Dr Habib Boukerche (Faculté de Médecine René Laënnec, Lyon, France) for their kind gifts of anti-αIIbβ3 (GPIIbIIIa) mAb clones., ANR-18-CE15-0001,Autoimmuni-B,Etude de la rupture de tolérance dans une maladie humaine autoimmune médiée par les lymphocytes B(2018), ANR-14-CE16-0011,DROP-mAbs,Analyse en profondeur de répertoires d'anticorps par microfluidique en gouttelettes couplé à du séquençage haut-débit pour le diagnostic et la découverte d'anticorps thérapeutiques(2014), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-10-EQPX-0034,IPGG,Institut Pierre Gilles de Gennes pour la microfluidique(2010), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur [Paris]-Université Paris Cité (UPCité), and CHU Henri Mondor [Créteil]

Subjects
Blood Platelets, Platelets, Purpura, Thrombocytopenic, Idiopathic, [SDV.IMM] Life Sciences [q-bio]/Immunology, Autoimmune diseases, Plasma Cells, Adaptive immunity, Autoimmunity, General Medicine, Therapeutics, Immunoglobulin G, hemic and lymphatic diseases, Splenectomy, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Autoantibodies
Abstract

The major therapeutic goal for immune thrombocytopenic purpura (ITP) is to restore normal platelet counts using drugs to promote platelet production or by interfering with mechanisms responsible for platelet destruction. Eighty percent of patients with ITP possess anti???integrin ??IIb??3 IgG autoantibodies that cause platelet opsonization and phagocytosis. The spleen is considered the primary site of autoantibody production by autoreactive B cells and platelet destruction. The immediate failure in approximately 50% of patients to recover a normal platelet count after anti-CD20 rituximab-mediated B cell depletion and splenectomy suggests that autoreactive, rituximab-resistant, IgG-secreting B cells (IgG-SCs) reside in other anatomical compartments. We analyzed more than 3,300 single IgG-SCs from spleen, bone marrow, and/or blood of 27 patients with ITP, revealing high interindividual variability in affinity for ??IIb??3, with variations over 3 logs. IgG-SC dissemination and range of affinities were, however, similar for each patient. Longitudinal analysis of autoreactive IgG-SCs upon treatment with the anti-CD38 mAb daratumumab demonstrated variable outcomes, from complete remission to failure with persistence of high-affinity anti?????IIb??3 IgG-SCs in the bone marrow. This study demonstrates the existence and dissemination of high-affinity autoreactive plasma cells in multiple anatomical compartments of patients with ITP that may cause the failure of current therapies., The Journal of Clinical Investigation, 132 (12), ISSN:1558-8238, ISSN:0021-9738

Published
2022
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2. Specificity of mouse and human Fcgamma receptors and their polymorphic variants for IgG subclasses of different species

Author

Yu Wang, Vanessa Krémer, Bruno Iannascoli, Odile Richard‐Le Goff, David A. Mancardi, Leoni Ramke, Luc Chaisemartin, Pierre Bruhns, Friederike Jönsson, Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS), This work was supported by a Jeunes Chercheuses/Jeunes Chercheurs grant from the Agence National de la Recherche (ANR- 16-CE15-0012), Institut National de la Recherche Médicale (INSERM) and Institut Pasteur. YW and VK are part of the Pasteur–Paris University (PPU) International PhD Program. This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 665807, and from the Labex Milieu Intérieur, Institut Pasteur. For the purpose of open access, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission., ANR-16-CE15-0012,PlanA,Rôle des plaquettes et leurs interactions dans les réactions anaphylactiques(2016), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015), Jönsson, Friederike, Rôle des plaquettes et leurs interactions dans les réactions anaphylactiques - - PlanA2016 - ANR-16-CE15-0012 - AAPG2016 - 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, and Institut Pasteur International Docotal Program - PASTEURDOC - - H20202015-10-01 - 2020-10-01 - 665807 - VALID

Subjects
Hybridomas, [SDV.IMM] Life Sciences [q-bio]/Immunology, Fcγ receptors, cross-binding, IgG, Receptors, IgG, Immunology, Mice, Transgenic, 3. Good health, immune complexes, Mice, Immunoglobulin G, Animals, Humans, Immunology and Allergy, [SDV.IMM]Life Sciences [q-bio]/Immunology, Carrier Proteins
Abstract

International audience; Immunoglobulin G (IgG) is the predominant antibody class generated during infections and used for the generation of therapeutic antibodies. Antibodies are mainly characterized in or generated from animal models that support particular infections, respond to particular antigens or allow the generation of hybridomas. Due to the availability of numerous transgenic mouse models and the ease of performing bioassays with human blood cells in vitro, most antibodies from species other than mice and humans are tested in vitro using human cells and/or in vivo using mice. In this process, it is expected, but not yet systematically documented, that IgG from these species interact with human or mouse IgG receptors (FcRs). In this study, we undertook a systematic assessment of binding specificities of IgG from various species to the families of mouse and human FcRs, including their polymorphic variants. Our results document the specific binding patterns for each of these IgG (sub)classes, reveal possible caveats of antibody-based immunoassays, and will be a useful reference for the transition from one animal model to preclinical mouse models or human cell-based bioassays.

Published
2022
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3. An Engineered Human Fc variant With Exquisite Selectivity for FcγRIIIaV158 Reveals That Ligation of FcγRIIIa Mediates Potent Antibody Dependent Cellular Phagocytosis With GM-CSF-Differentiated Macrophages

Author

Tae Hyun Kang, Chang-Han Lee, George Delidakis, Jiwon Jung, Odile Richard-Le Goff, Jiwon Lee, Jin Eyun Kim, Wissam Charab, Pierre Bruhns, George Georgiou, University of Texas at Austin [Austin], Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the Clayton Foundation (Austin, TX, USA), the Institut Pasteur and the Institut National de la Santé et de la Recherche Médicale (Paris, France)., and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
lcsh:Immunologic diseases. Allergy, 0301 basic medicine, FcgR, Immunology, Fc engineering, macrophage, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, Avidity, Receptor, Antibody-dependent cell-mediated cytotoxicity, biology, Chemistry, Effector, Monocyte, ADCP, Immune complex, Cell biology, 030104 developmental biology, medicine.anatomical_structure, monocyte, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, lcsh:RC581-607, 030215 immunology
Abstract

International audience; IgG antibodies mediate the clearance of target cells via the engagement of Fc gamma receptors (FcγRs) on effector cells by eliciting antibody-dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP, respectively). Because (i) the IgG Fc domain binds to multiple FcγRs with varying affinities; (ii) even low Fc:FcγRs affinity interactions can play a significant role when antibodies are engaged in high avidity immune complexes and (iii) most effector cells express multiple FcγRs, the clearance mechanisms that can be mediated by individual FcγR are not well-understood. Human FcγRIIIa (hFcγRIIIa; CD16a), which exists as two polymorphic variants at position 158, hFcγRIIIaV158 and hFcγRIIIaF158, is widely considered to only trigger ADCC, especially with natural killer (NK) cells as effectors. To evaluate the role of hFcγRIIIa ligation in myeloid-derived effector cells, and in particular on macrophages and monocytes which express multiple FcγRs, we engineered an aglycosylated engineered human Fc (hFc) variant, Fc3aV, which binds exclusively to hFcγRIIIaV158. Antibodies formatted with the Fc3aV variant bind to the hFcγRIIIaV158 allotype with a somewhat lower KD than their wild type IgG1 counterparts, but not to any other hFcγR. The exceptional selectivity for hFcγRIIIaV158 was demonstrated by SPR using increased avidity, dimerized GST-fused versions of the ectodomains of hFcγRs and from the absence of binding of large immune complex (IC) to CHO cells expressing each of the hFcγRs, including notably, the FcγRIIIaF158 variant or the highly homologous FcγRIIIb. We show that even though monocyte-derived GM-CSF differentiated macrophages express hFcγRIIIa at substantially lower levels than the other two major activating receptors, namely hFcγRI or hFcγRIIa, Fc3aV-formatted Rituximab and Herceptin perform ADCP toward CD20- and Her2-expressing cancer cells, respectively, at a level comparable to that of the respective wild-type antibodies. We further show that hFcγRIIIa activation plays a significant role on ADCC by human peripheral monocytes. Our data highlight the utility of Fc3aV and other similarly engineered exquisitely selective, aglycosylated Fc variants toward other hFcγRs as tools for the detailed molecular understanding of hFcγR biology.

Published
2019
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4. IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions

Author

Bianca Balbino, George Delidakis, Tae Hyun Kang, Makiko Watanabe, Kendra Triplett, Anja Lux, Navin Varadarajan, Odile Richard-Le Goff, Oana I. Lungu, Pierre Bruhns, George Georgiou, Corrine Alford, Gabrielle Romain, Margaret A. Lindorfer, Wissam Charab, Falk Nimmerjahn, Yan Jessie Zhang, Hidetaka Tanno, Wupeng Yan, Nicholas M. Marshall, Moses Donkor, Chang-Han Lee, Jiwon Lee, Ronald P. Taylor, Biliana Todorova, University of Texas at Austin [Austin], University of Houston, Anticorps en Thérapie et Pathologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Erlangen-Nürnberg [Germany], University of Virginia School of Medicine [US], Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), University of Virginia, Department of Biochemistry and Molecular Genetics (xxx), University of Virginia [Charlottesville], We thank Y. Tanno for assistance with protein expression, A. Bui for assistance with liquid chromatography–tandem mass spectrometry, P. Tucker (University of Texas at Austin) for cancer cell lines, D. Lee (MD Anderson Cancer Center) for patient-derived primary acute lymphocytic leukemia cells, the Macromolecular Crystallography Facility of the University of Texas at Austin, the Berkeley Center for Structural Biology, the Advanced Light Source (supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under contract DE-AC02-05CH11231), the Proteomics Facility at the University of Texas at Austin (supported by grant RP110782 from the Cancer Prevention Research Training Program), and A. Nicola and the Plate-Forme d'Imagerie Dynamique (Institut Pasteur, Paris) for help with the bioluminescence experiments. Supported by the Clayton Foundation, the Institut Pasteur (P.B. laboratory), the Institut National de la Santé et de la Recherche Médicale (P.B. laboratory), the European Research Council Seventh Frame-work Program (ERC-2013-CoG 616050 for the P.B. laboratory), the Pasteur–Paris University International PhD program (B.B.), the Cancer Prevention Research Training Program (RP140108 to M.D., RP160015 to H.T., and RP130570 to N.V.), the American Cancer Society (123506-PF-13-354-01-CDD to N.M.), Uehara Memorial Foundation (H.T.), Japan Society for the Promotion of Science (H.T.), Deutsche Forschungsgemeinschaft (CRC1181-A07 to F.N.), the US National Institutes of Health (R01CA174385 to N.V., and R01 GM104896 to Y.J.Z.) and the Welch Foundation (F-1778 to Y.J.Z.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Cancer Prevention and Research Institute of Texas., European Project: 616050,EC:FP7:ERC,ERC-2013-CoG,MYELOSHOCK(2014), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Virginia, Martin, Marie, and Role of myeloid cells, their mediators and their antibody receptors in allergic shock (anaphylaxis) using humanized mouse models and clinical samples - MYELOSHOCK - - EC:FP7:ERC2014-09-01 - 2019-08-31 - 616050 - VALID

Subjects
Cytotoxicity, Immunologic, 0301 basic medicine, Cellular immunity, MESH: Complement C1q, MESH: Immunotherapy, Crystallography, X-Ray, Mass Spectrometry, MESH: Antibodies, Monoclonal, Mice, Tandem Mass Spectrometry, Neoplasms, Immunology and Allergy, MESH: Animals, MESH: Neoplasms, Cytotoxicity, Receptor, MESH: Phagocytosis, MESH: Crystallization, MESH: Immunoglobulin G, biology, Effector, Antibodies, Monoclonal, MESH: Enzyme-Linked Immunosorbent Assay, MESH: Chromatography, Gel, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Burkitt Lymphoma, 3. Good health, Cell biology, MESH: Surface Plasmon Resonance, Chromatography, Gel, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunotherapy, Lymphoma, Large B-Cell, Diffuse, Antibody, Crystallization, Lymphoma, B-Cell, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Enzyme-Linked Immunosorbent Assay, In Vitro Techniques, MESH: Receptors, IgG, MESH: Immunoglobulin Fc Fragments, 03 medical and health sciences, Classical complement pathway, Immune system, Phagocytosis, Cell Line, Tumor, Animals, Humans, MESH: Cytotoxicity, Immunologic, MESH: Mice, MESH: Lymphoma, B-Cell, MESH: In Vitro Techniques, MESH: Mass Spectrometry, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, Complement C1q, Receptors, IgG, MESH: Tandem Mass Spectrometry, Surface Plasmon Resonance, MESH: Crystallography, X-Ray, Immunoglobulin Fc Fragments, Complement system, MESH: Burkitt Lymphoma, 030104 developmental biology, Immunoglobulin G, biology.protein, MESH: Lymphoma, Large B-Cell, Diffuse, MESH: Chromatography, Liquid, Chromatography, Liquid
Abstract

International audience; Engineered crystallizable fragment (Fc) regions of antibody domains, which assume a unique and unprecedented asymmetric structure within the homodimeric Fc polypeptide, enable completely selective binding to the complement component C1q and activation of complement via the classical pathway without any concomitant engagement of the Fcγ receptor (FcγR). We used the engineered Fc domains to demonstrate in vitro and in mouse models that for therapeutic antibodies, complement-dependent cell-mediated cytotoxicity (CDCC) and complement-dependent cell-mediated phagocytosis (CDCP) by immunological effector molecules mediated the clearance of target cells with kinetics and efficacy comparable to those of the FcγR-dependent effector functions that are much better studied, while they circumvented certain adverse reactions associated with FcγR engagement. Collectively, our data highlight the importance of CDCC and CDCP in monoclonal-antibody function and provide an experimental approach for delineating the effect of complement-dependent effector-cell engagement in various therapeutic settings.

Published
2017
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5. GATA-3 promotes T-cell specification by repressing B-cell potential in pro–T cells in mice

Author

Ana Cumano, Odile Richard-Le Goff, Roel G. J. Klein Wolterink, Rudolf W. Hendriks, Fabrice Lemaître, Milena Hasan, James P. Di Santo, Marcos E. García-Ojeda, Immunité Innée, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement des Lymphocytes, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Dynamiques des Réponses Immunes, Centre d'Immunologie Humaine (CIH), This work was supported by a fellowship from the Pasteur Foundation (M.E.G.-O.), by grants from the Huygens Scholarship Program and the Royal Netherlands Academy for Arts and Sciences (both the Netherlands) and by the Ligue Nationale Contre le Cancer (France, R.G.J.K.W.). This work was also supported by grants from the Institut Pasteur, the Inserm, and the Ligue Nationale Contre le Cancer (all in France, J.P.D.)., Pulmonary Medicine, Immunology, and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, MESH: Signal Transduction, Receptors, Antigen, T-Cell, alpha-beta, MESH: Flow Cytometry, MESH: Receptor, Notch1, Biochemistry, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Inside Blood, b-lymphocytes, MESH: Animals, Receptor, Notch1, Cells, Cultured, Mice, Knockout, 0303 health sciences, MESH: Receptors, Antigen, T-Cell, alpha-beta, Cell Differentiation, Hematology, MESH: Transcription Factors, Flow Cytometry, Cell biology, medicine.anatomical_structure, embryonic structures, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, biological phenomena, cell phenomena, and immunity, medicine.symptom, Signal Transduction, MESH: Cells, Cultured, MESH: Cell Differentiation, T cell, Immunology, gata3 gene, GATA3 Transcription Factor, Thymus Gland, Biology, 03 medical and health sciences, MESH: B-Lymphocytes, MESH: GATA3 Transcription Factor, medicine, Animals, Notch1 signaling, Cell Lineage, Transcription factor, t-lymphocytes, MESH: Mice, B cell, 030304 developmental biology, Cell Biology, MESH: Thymus Gland, MESH: Cell Lineage, MESH: Male, MESH: T-Lymphocytes, Mechanism of action, MESH: Female, 030215 immunology, Transcription Factors
Abstract

International audience; Transcription factors orchestrate T-lineage differentiation in the thymus. One critical checkpoint involves Notch1 signaling that instructs T-cell commitment at the expense of the B-lineage program. While GATA-3 is required for T-cell specification, its mechanism of action is poorly understood. We show that GATA-3 works in concert with Notch1 to commit thymic progenitors to the T-cell lineage via 2 distinct pathways. First, GATA-3 orchestrates a transcriptional “repertoire” that is required for thymocyte maturation up to and beyond the pro–T-cell stage. Second, GATA-3 critically suppresses a latent B-cell potential in pro–T cells. As such, GATA-3 is essential to sealing in Notch-induced T-cell fate in early thymocyte precursors by promoting T-cell identity through the repression of alternative developmental options.

Published
2013
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6. Cutting Edge: A Thymocyte-Thymic Epithelial Cell Cross-Talk Dynamically Regulates Intrathymic IL-7 Expression In Vivo

Author

Nuno L. Alves, Jean-Jacques Mention, Nicholas D. Huntington, Odile Richard-Le Goff, James P. Di Santo, Cytokines et Développement Lymphoïde, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Biologia Molecular e Celular - institute for molecular and cell biology [Porto, Portugal] (IBMC), Universidade do Porto = University of Porto, This work was supported in part by Institut Pasteur, Institut National de la Santé et de la Recherche Médicale, the Fondation pour le Recherche Médicale (SPF20081214865), the Ligue Nationale Contre le Cancer, and the Foundation for Science and Technology (SFRH/45932/2008 and Program Ciência 2008)., and RICHARD-LE GOFF, ODILE

Subjects
Yellow fluorescent protein, Cellular differentiation, T-Lymphocytes, Gene Expression, MESH: Flow Cytometry, Cell Separation, MESH: T-Lymphocyte Subsets, MESH: Mice, Knockout, Mice, T-Lymphocyte Subsets, Immunology and Allergy, MESH: Animals, Thymopoietin, Regulation of gene expression, Mice, Knockout, medicine.diagnostic_test, biology, Cell Differentiation, hemic and immune systems, Flow Cytometry, Immunohistochemistry, MESH: Gene Expression Regulation, Cell biology, Thymocyte, Haematopoiesis, MESH: Epithelial Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, tissues, MESH: Cell Differentiation, medicine.medical_specialty, MESH: Gene Expression, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, education, MESH: Receptor Cross-Talk, Thymus Gland, MESH: Cell Separation, Flow cytometry, Internal medicine, medicine, Animals, Progenitor cell, MESH: Mice, Interleukin-7, Epithelial Cells, MESH: Immunohistochemistry, Receptor Cross-Talk, MESH: Thymus Gland, MESH: Interleukin-7, Endocrinology, MESH: T-Lymphocytes, Gene Expression Regulation, biology.protein
Abstract

Thymic epithelial cells (TECs) are the predominant intrathymic source of the essential thymopoietin IL-7. Whether thymocyte-TEC interactions have a role in the regulation of IL-7 expression is not known. By exploiting IL-7 reporter mice in which yellow fluorescent protein expression identifies TECs expressing high levels of IL-7 (Il7+ TECs), we show that Il7+ TECs segregate from emerging medullary TECs during thymic organogenesis. Although Il7+ TECs normally diminish with age, we found that Il7+ TECs are markedly retained in alymphoid Rag2−/−Il2rg−/− IL-7 reporter mice that manifest a profound thymopoietic arrest. Transfer of Tcra−/− or wild-type (but not Rag2−/−) hematopoietic progenitors to alymphoid IL-7 reporter recipients normalizes the frequency of Il7+ TECs and re-establishes cortical TEC/medullary TEC segregation. Although thymocyte-derived signals are often considered stimulatory for TEC maturation, our findings identify a negative feedback mechanism in which signals derived from TCRβ-selected thymocytes modulate TEC-dependent IL-7 expression.

Published
2010
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7. CD11cloB220+ interferon-producing killer dendritic cells are activated natural killer cells

Author

Ofer Mandelboim, Odile Richard-Le Goff, Christian A. J. Vosshenrich, Sarah Lesjean-Pottier, Milena Hasan, Erwan Corcuff, James P. Di Santo, Cytokines et Développement Lymphoïde, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, This work was supported by grants from the Institut Pasteur and the Institut National de la Santé et de la Recherche Médicale, and as an Equipe Labelisé of the Ligue National Contre le Cancer., and RICHARD-LE GOFF, ODILE

Subjects
MESH: Spleen, MESH: Interleukin-15, Lymphocyte Activation, MESH: Mice, Knockout, Interleukin 21, Mice, Interferon, Immunology and Allergy, MESH: Animals, Interleukin-15, Mice, Knockout, Immunity, Cellular, MESH: Dendritic Cells, Interleukin, hemic and immune systems, Natural killer T cell, MESH: Crosses, Genetic, Killer Cells, Natural, MESH: Leukocyte Common Antigens, Interleukin 15, Interleukin 12, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Immunity, Innate, medicine.drug, MESH: Killer Cells, Natural, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, MESH: Lymphocyte Subsets, CD11c, chemical and pharmacologic phenomena, Biology, Major histocompatibility complex, MESH: Immunity, Cellular, MESH: Mice, Inbred C57BL, medicine, Animals, MESH: Lymphocyte Activation, MESH: Mice, Crosses, Genetic, Histocompatibility Antigens Class II, Brief Definitive Report, Dendritic Cells, Molecular biology, Immunity, Innate, Lymphocyte Subsets, CD11c Antigen, Mice, Inbred C57BL, biology.protein, MESH: CD11c Antigen, MESH: Histocompatibility Antigens Class II, Leukocyte Common Antigens, Brief Definitive Reports, Spleen
Abstract

Interferon-producing killer dendritic cells (IKDCs) are a recently described subset of CD11c(lo)B220(+) cells that share phenotypic and functional properties of DCs and natural killer (NK) cells (Chan, C.W., E. Crafton, H.N. Fan, J. Flook, K. Yoshimura, M. Skarica, D. Brockstedt, T.W. Dubensky, M.F. Stins, L.L. Lanier, et al. 2006. Nat. Med. 12:207-213; Taieb, J., N. Chaput, C. Menard, L. Apetoh, E. Ullrich, M. Bonmort, M. Pequignot, N. Casares, M. Terme, C. Flament, et al. 2006. Nat. Med. 12:214-219). IKDC development appears unusual in that cytokines using the interleukin (IL)-2 receptor beta (IL-2Rbeta) chain but not those using the common gamma chain (gamma(c)) are necessary for their generation. By directly comparing Rag2(-/-)gamma(c)(-/y), Rag2(-/-)IL-2Rbeta(-/-), Rag2(-/-)IL-15(-/-), and Rag2(-/-)IL-2(-/-) mice, we demonstrate that IKDC development parallels NK cell development in its strict IL-15 dependence. Moreover, IKDCs uniformly express NK-specific Ncr-1 transcripts (encoding NKp46), whereas NKp46(+) cells are absent in Ncr1(gfp/+)gamma(c)(-/y) mice. Distinguishing features of IKDCs (CD11c(lo)B220(+)MHC-II(+)) were carefully examined on developing NK cells in the bone marrow and on peripheral NK cells. As B220 expression was heterogeneous, defining B220(lo) versus B220(hi) NK1.1(+) NK cells could be considered as arbitrary, and few phenotypic differences were noted between NK1.1(+) NK cells bearing different levels of B220. CD11c expression did not correlate with B220 or major histocompatibility complex (MHC) class II (MHC-II) expression, and most MHC-II(+) NK1.1(+) cells did not express B220 and were thus not IKDCs. Finally, CD11c, MHC-II, and B220 levels were up-regulated on NK1.1(+) cells upon activation in vitro or in vivo in a proliferation-dependent fashion. Our data suggest that the majority of CD11c(lo)B220(+) "IKDC-like" cells represent activated NK cells.

Published
2007
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8. A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127

Author

Benedita Rocha, Ana Cumano, Sophie Ezine, Erwan Corcuff, Lars Rogge, Marcos E. García-Ojeda, Odile Richard-Le Goff, Christian A. J. Vosshenrich, Sandrine I. Samson-Villeger, Delphine Guy-Grand, James P. Di Santo, Valérie Pasqualetto, Laurence Enault, Cytokines et Développement Lymphoïde, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Differenciation Thymique et Physiologie des Lymphocytes T (U591), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Développement des Lymphocytes, Immunorégulation, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Differenciation Thymique et Physiologie des Lymphocytes T ( U591 ), 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 Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS )

Subjects
Cytotoxicity, Immunologic, MESH: Signal Transduction, MESH : GATA3 Transcription Factor, MESH : Cytokines, MESH : Cytotoxicity, Immunologic, MESH : Interleukin-7 Receptor alpha Subunit, Interleukin 21, Mice, 0302 clinical medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, MESH: Animals, 0303 health sciences, MESH: Cytokines, MESH : Lymphocyte Subsets, MESH : Mice, Nude, Interleukin, virus diseases, Cell Differentiation, hemic and immune systems, Natural killer T cell, MESH : Mice, Transgenic, Cell biology, Killer Cells, Natural, MESH : Immunophenotyping, Interleukin 12, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : Killer Cells, Natural, MESH : Cell Differentiation, Signal Transduction, MESH : Interleukin-7, MESH: Cell Differentiation, MESH: Killer Cells, Natural, MESH: Immunophenotyping, MESH: Mice, Transgenic, Immunology, MESH: Lymphocyte Subsets, Mice, Nude, Mice, Transgenic, chemical and pharmacologic phenomena, MESH : Mice, Inbred C57BL, GATA3 Transcription Factor, Thymus Gland, Biology, CD16, Immunophenotyping, Interleukin-7 Receptor alpha Subunit, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH : Mice, MESH: GATA3 Transcription Factor, MESH: Mice, Nude, Animals, Humans, MESH : Thymus Gland, MESH: Cytotoxicity, Immunologic, MESH: Mice, 030304 developmental biology, MESH : Signal Transduction, Lymphokine-activated killer cell, MESH: Humans, Cell growth, Interleukin-7, MESH : Humans, MESH: Interleukin-7 Receptor alpha Subunit, MESH: Thymus Gland, Lymphocyte Subsets, MESH: Interleukin-7, Mice, Inbred C57BL, Myeloid-derived Suppressor Cell, MESH : Animals, 030215 immunology
Abstract

International audience; Natural killer (NK) cell development is thought to occur in the bone marrow. Here we identify the transcription factor GATA-3 and CD127 (IL-7R alpha) as molecular markers of a pathway of mouse NK cell development that originates in the thymus. Thymus-derived CD127+ NK cells repopulated peripheral lymphoid organs, and their homeostasis was strictly dependent on GATA-3 and interleukin 7. The CD127+ NK cells had a distinct phenotype (CD11b(lo) CD16- CD69(hi) Ly49(lo)) and unusual functional attributes, including reduced cytotoxicity but considerable cytokine production. Those characteristics are reminiscent of human CD56(hi) CD16- NK cells, which we found expressed CD127 and had more GATA-3 expression than human CD56+ CD16+ NK cells. We propose that bone marrow and thymic NK cell pathways generate distinct mouse NK cells with properties similar to those of the two human CD56 NK cell subsets.

Published
2006
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