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11 results on '"MESH: Immunologic Memory"'

1. Trained immunity, tolerance, priming and differentiation: distinct immunological processes

Author

Boris Novakovic, Andreas Schlitzer, Giuseppe Matarese, Zahi A. Fayad, Willem J. M. Mulder, Henk Stunnenberg, Andrew R. DiNardo, Niels P. Riksen, Joachim L. Schultze, Christine Stabell Benn, Joseph C. Sun, Eva Kaufmann, Shabaana A. Khader, Michael H. Sieweke, Siroon Bekkering, Stephanie Fanucchi, Luis B. Barreiro, Maziar Divangahi, Mihai G. Netea, Reinout van Crevel, Jordi Ochando, Peter Aaby, Shruti Naik, Leo A. B. Joosten, Triantafyllos Chavakis, Musa M. Mhlanga, Eicke Latz, David L. Williams, Jos W. M. van der Meer, Luke A. J. O'Neill, Ramnik J. Xavier, Nigel Curtis, Robert W. Sauerwein, Kate L. Jeffrey, Edward R. Sherwood, Elaine Fuchs, Sebastian Weis, Nargis Khan, Melanie Hamon, Raphael Duivenwoorden, Keiko Ozato, Simone J.C.F.M. Moorlag, Jorge Domínguez-Andrés, Frank L. van de Veerdonk, Precision Medicine, ICMS Core, McGill University Health Center [Montreal] (MUHC), Bandim Health Project, International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH Network), Washington University in Saint Louis (WUSTL), The University of Chicago Medicine [Chicago], Radboud University Medical Center [Nijmegen], Technische Universität Dresden = Dresden University of Technology (TU Dresden), University of Melbourne, Baylor College of Medicine (BCM), Baylor University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Eindhoven University of Technology [Eindhoven] (TU/e), University of Cape Town, Rockefeller University [New York], Chromatine et Infection - Chromatin and Infection, Institut Pasteur [Paris] (IP), Harvard Medical School [Boston] (HMS), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Trinity Biomedical Sciences Institute, School of Biochemistry & Immunology, National Institute of Child Health and Human Development [Bethesda], National Institutes of Health, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Universität Bonn = University of Bonn, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biotechnology Center, and Center for Regenerative Therapies Dresden (CRTD), Max Delbrück Centrum für Molekulare Medizin (MDC), University of Southern Denmark (SDU), Radboud University [Nijmegen], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Jena University Hospital [Jena], East Tennessee State University (ETSU), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts Institute of Technology (MIT), Divangahi, M., Aaby, P., Khader, S. A., Barreiro, L. B., Bekkering, S., Chavakis, T., van Crevel, R., Curtis, N., Dinardo, A. R., Dominguez-Andres, J., Duivenwoorden, R., Fanucchi, S., Fayad, Z., Fuchs, E., Hamon, M., Jeffrey, K. L., Khan, N., Joosten, L. A. B., Kaufmann, E., Latz, E., Matarese, G., van der Meer, J. W. M., Mhlanga, M., Moorlag, S. J. C. F. M., Mulder, W. J. M., Naik, S., Novakovic, B., O'Neill, L., Ochando, J., Ozato, K., Riksen, N. P., Sauerwein, R., Sherwood, E. R., Schlitzer, A., Schultze, J. L., Sieweke, M. H., Benn, C. S., Stunnenberg, H., Sun, J., van de Veerdonk, F. L., Weis, S., Williams, D. L., Xavier, R., Netea, M. G., Institut Pasteur [Paris], Consiglio Nazionale delle Ricerche (CNR), University of Bonn, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft, Radboud university [Nijmegen], Hamon, Melanie, and ACS - Atherosclerosis & ischemic syndromes

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], animal diseases, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Priming (immunology), Adaptive Immunity, 0302 clinical medicine, Immunology and Allergy, MESH: Animals, ComputingMilieux_MISCELLANEOUS, immunology [BCG Vaccine], Vaccination, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], Cell Differentiation, Common framework, [SDV] Life Sciences [q-bio], MESH: BCG Vaccine, BCG Vaccine, MESH: Immunologic Memory, MESH: Immunity, Innate, MESH: Cell Differentiation, MESH: Immune Tolerance, Immunology, education, immunology [Adaptive Immunity], chemical and pharmacologic phenomena, Biology, Article, 03 medical and health sciences, Immune system, Immunity, Immune Tolerance, Animals, Humans, ddc:610, Molecular Biology, MESH: Humans, immunology [Immune Tolerance], Cell Biology, MESH: Vaccination, biochemical phenomena, metabolism, and nutrition, Immunity, Innate, immunology [Immunologic Memory], immunology [Immunity, Innate], Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030104 developmental biology, bacteria, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Neuroscience, Immunologic Memory, MESH: Adaptive Immunity, 030215 immunology
Abstract

The similarities and differences between trained immunity and other immune processes are the subject of intense interrogation. Therefore, a consensus on the definition of trained immunity in both in vitro and in vivo settings, as well as in experimental models and human subjects, is necessary for advancing this field of research. Here we aim to establish a common framework that describes the experimental standards for defining trained immunity.

Published
2021
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2. Tissue-resident CD8 + T cells drive compartmentalized and chronic autoimmune damage against CNS neurons

Author

David Frieser, Aurora Pignata, Leila Khajavi, Danielle Shlesinger, Carmen Gonzalez-Fierro, Xuan-Hung Nguyen, Alexander Yermanos, Doron Merkler, Romana Höftberger, Virginie Desestret, Katharina M. Mair, Jan Bauer, Frederick Masson, Roland S. Liblau, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Université de Genève = University of Geneva (UNIGE), Medizinische Universität Wien = Medical University of Vienna, Mécanismes en sciences intégratives du vivant (MeLiS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Masson, Frédéric

Subjects
[SDV] Life Sciences [q-bio], MESH: Autoimmune Diseases* / pathology, MESH: CD8-Positive T-Lymphocytes, [SDV]Life Sciences [q-bio], MESH: Immunologic Memory, MESH: Central Nervous System, General Medicine
Abstract

The mechanisms underlying the chronicity of autoimmune diseases of the central nervous system (CNS) are largely unknown. In particular, it is unclear whether tissue-resident memory T cells (TRM) contribute to lesion pathogenesis during chronic CNS autoimmunity. Here, we observed that a high frequency of brain-infiltrating CD8+T cells exhibit a TRM-like phenotype in human autoimmune encephalitis. Using mouse models of neuronal autoimmunity and a combination of T single-cell transcriptomics, high-dimensional flow cytometry, and histopathology, we found that pathogenic CD8+T cells behind the blood-brain barrier adopt a characteristic TRMdifferentiation program, and we revealed their phenotypic and functional heterogeneity. In the diseased CNS, autoreactive tissue-resident CD8+T cells sustained focal neuroinflammation and progressive loss of neurons, independently of recirculating CD8+T cells. Consistently, a large fraction of autoreactive tissue-resident CD8+T cells exhibited proliferative potential as well as proinflammatory and cytotoxic properties. Persistence of tissue-resident CD8+T cells in the CNS and their functional output, but not their initial differentiation, were crucially dependent on CD4+T cells. Collectively, our results point to tissue-resident CD8+T cells as essential drivers of chronic CNS autoimmunity and suggest that therapies targeting this compartmentalized autoreactive T cell subset might be effective for treating CNS autoimmune diseases.

Published
2022
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3. Robust and Functional Immune Memory Up to 9 Months After SARS-CoV-2 Infection: A Southeast Asian Longitudinal Cohort

Author

Hoa Thi My Vo, Alvino Maestri, Heidi Auerswald, Sopheak Sorn, Sokchea Lay, Heng Seng, Sotheary Sann, Nisa Ya, Polidy Pean, Philippe Dussart, Olivier Schwartz, Sovann Ly, Timothée Bruel, Sowath Ly, Veasna Duong, Erik A. Karlsson, Tineke Cantaert, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Communicable Disease Department [Phnom Penh] (CDC MOH), Ministry of Health [Mozambique], Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), The Howard Hughes Medical Institute (HHMI)–Wellcome Trust (208710/Z/17/Z to TC), « URGENCE COVID-19 » fundraising campaign of Institut Pasteur (TC, HA, and PD). HA is supported by the German Centre for International Migration and Development (CIM)., Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Vaccine Research Institute (VRI)

Subjects
CD4-Positive T-Lymphocytes, Immunology, MESH: Spike Glycoprotein, Coronavirus, CD8-Positive T-Lymphocytes, B cell immunity, Antibodies, Viral, MESH: Phosphoproteins, long term immune response, MESH: Antibodies, Neutralizing, MESH: Immunity, Cellular, Immunology and Allergy, Coronavirus Nucleocapsid Proteins, Humans, MESH: COVID-19, MESH: Coronavirus Nucleocapsid Proteins, MESH: SARS-CoV-2, MESH: Immunity, Humoral, B-Lymphocytes, Immunity, Cellular, MESH: Humans, T cell immunity, SARS-CoV-2, MESH: Cambodia, COVID-19, MESH: CD4-Positive T-Lymphocytes, RC581-607, Phosphoproteins, Antibodies, Neutralizing, MESH: CD8-Positive T-Lymphocytes, Immunity, Humoral, antibody effector function, Spike Glycoprotein, Coronavirus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Immunologic Memory, Immunologic diseases. Allergy, Cambodia, Immunologic Memory, MESH: Antibodies, Viral
Abstract

The duration of humoral and cellular immune memory following SARS-CoV-2 infection in populations in least developed countries remains understudied but is key to overcome the current SARS-CoV-2 pandemic. Sixty-four Cambodian individuals with laboratory-confirmed infection with asymptomatic or mild/moderate clinical presentation were evaluated for Spike (S)-binding and neutralizing antibodies and antibody effector functions during acute phase of infection and at 6-9 months follow-up. Antigen-specific B cells, CD4+ and CD8+ T cells were characterized, and T cells were interrogated for functionality at late convalescence. Anti-S antibody titers decreased over time, but effector functions mediated by S-specific antibodies remained stable. S- and nucleocapsid (N)-specific B cells could be detected in late convalescence in the activated memory B cell compartment and are mostly IgG+. CD4+ and CD8+ T cell immune memory was maintained to S and membrane (M) protein. Asymptomatic infection resulted in decreased antibody-dependent cellular cytotoxicity (ADCC) and frequency of SARS-CoV-2-specific CD4+ T cells at late convalescence. Whereas anti-S antibodies correlated with S-specific B cells, there was no correlation between T cell response and humoral immune memory. Hence, all aspects of a protective immune response are maintained up to nine months after SARS-CoV-2 infection and in the absence of re-infection.

Published
2022
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4. H3K4me1 Supports Memory-like NK Cells Induced by Systemic Inflammation

Author

Tiphaine M. N. Camarasa, Catherine Fitting, Melanie Hamon, Jean-Marc Cavaillon, Orhan Rasid, Christine Chevalier, Chromatine et Infection - Chromatin and Infection, Institut Pasteur [Paris], Cytokines et Inflammation, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Work in the M.A.H. laboratory received financial support from Institut Pasteur and the French National Research Agency (ANR-EPIBACTIN). O.R. was supported by a stipend from the Pasteur – Paris University International PhD Program for part of this work. T.M.-N.C. is supported by a fellowship from the Foundation for Medical Research (Mariane Josso Prize)., We would like to thank Olivier Dussurget and Emmanuel Lemichez for the kind gift of the luminescent E. coli, Thomas Kohler and Sven Hammerschmidt for the S. pneumoniae strain, and Ignacio Santecchia for technical assistance with E. coli culture., ANR-17-CE12-0007,EpiBactIn,Modifications epigenomiques induites par l'interaction hote-bacteries(2017), and Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, MESH: Inflammation, Male, Adoptive cell transfer, Histone methyltransferase activity, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Stimulation, NK cells, Systemic inflammation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, sepsis, Histones, Mice, 0302 clinical medicine, MESH: Animals, lcsh:QH301-705.5, Escherichia coli Infections, MESH: Histones, biology, MESH: Escherichia coli, NK cell memory, Cell biology, Killer Cells, Natural, Histone, Enhancer Elements, Genetic, MESH: Immunologic Memory, MESH: Immunity, Innate, medicine.symptom, epigenetic, MESH: Killer Cells, Natural, MESH: Interferon-gamma, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Interferon-gamma, medicine, Escherichia coli, Animals, Epigenetics, MESH: Mice, MESH: Escherichia coli Infections, Inflammation, Innate immune system, H3K4me1, Immunotherapy, MESH: Male, Endotoxemia, Immunity, Innate, 030104 developmental biology, lcsh:Biology (General), MESH: Endotoxemia, biology.protein, MESH: Enhancer Elements, Genetic, Immunologic Memory, 030217 neurology & neurosurgery
Abstract

Summary: Natural killer (NK) cells are unique players in innate immunity and, as such, an attractive target for immunotherapy. NK cells display immune memory properties in certain models, but the long-term status of NK cells following systemic inflammation is unknown. Here we show that following LPS-induced endotoxemia in mice, NK cells acquire cell-intrinsic memory-like properties, showing increased production of IFNγ upon specific secondary stimulation. The NK cell memory response is detectable for at least 9 weeks and contributes to protection from E. coli infection upon adoptive transfer. Importantly, we reveal a mechanism essential for NK cell memory, whereby an H3K4me1-marked latent enhancer is uncovered at the ifng locus. Chemical inhibition of histone methyltransferase activity erases the enhancer and abolishes NK cell memory. Thus, NK cell memory develops after endotoxemia in a histone methylation-dependent manner, ensuring a heightened response to secondary stimulation. : Rasid et al. show that sepsis-like systemic inflammation induces a type of long-lasting innate immune memory in NK cells, which can protect from E. coli infection. This is achieved by revealing an enhancer of IFNγ through histone monomethylation. Keywords: NK cells, NK cell memory, sepsis, epigenetic, H3K4me1

Published
2019
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5. Cell-mediated immunity to NAGLU transgene following intracerebral gene therapy in children with Mucopolysaccharidosis type IIIB syndrome

Author

Gougeon, Marie-Lise, Poirier-Beaudouin, Béatrice, Ausseil, Jérome, Zérah, Michel, Artaud, Cécile, Heard, Jean-Michel, Deiva, Kumaran, Tardieu, Marc, Département Infection et Epidémiologie - Department of Infection and Epidemiology, Institut Pasteur [Paris], Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Biothérapies pour les Maladies Neurodégénératives, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Service de Neurologie Pédiatrique [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institut Pasteur sponsored the study during thefirst 30 monthsand UniQure sponsored it for the following 36 months. Thestudy was supported by funds from the'Association FrançaiseContre les Myopathies (AFM)', the patients‘association'Vaincreles Maladies Lysosomales', the Institut Pasteur, the Conny MaevaCharitable Foundation, and a gift from the Akbaraly family., Institut Pasteur [Paris] (IP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin Bicêtre, and Institut Pasteur sponsored the study during thefirst 30 monthsand UniQure sponsored it for the following 36 months. Thestudy was supported by funds from the'Association Française Contre les Myopathies (AFM)', the patients‘association'Vaincreles Maladies Lysosomales', the Institut Pasteur, the Conny MaevaCharitable Foundation, and a gift from the Akbaraly family.

Subjects
NAGLU, T-Lymphocytes, [SDV]Life Sciences [q-bio], Genetic Vectors, Immunology, MESH: Mucopolysaccharidosis III / complications, T cells, cellular immunity, Lymphocyte Activation, MESH: Immunity, Cellular, MESH: Acetylglucosaminidase / genetics, MESH: Genetic Therapy / adverse effects, Mucopolysaccharidosis III, MESH: Mucopolysaccharidosis III / genetics, MESH: Child, Acetylglucosaminidase, MESH: Acetylglucosaminidase / immunology, Humans, Transgenes, MESH: Lymphocyte Activation, Child, Original Research, Immunity, Cellular, Drug Administration Routes, MESH: Cytokines / metabolism, MESH: Genetic Therapy / methods, MESH: Genetic Vectors / administration & dosage, AAV, Genetic Therapy, RC581-607, cytokines, MESH: Drug Administration Routes, MESH: Genetic Vectors / genetics, MESH: Immunologic Memory, MPS IIIB, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunologic diseases. Allergy, CNS, Immunologic Memory
Abstract

International audience; Mucopolysaccharidosis type IIIB syndrome (Sanfilippo disease) is a rare autosomic recessif disorder caused by mutations in the α-N-acetylglucosaminidase (NAGLU) gene coding for a lysosomal enzyme, leading to neurodegeneration and progressive deterioration of cognitive abilities in affected children. To supply the missing enzyme, several recent human gene therapy trials relied on the deposit of adeno-associated virus (AAV) vectors directly into the brain. We reported safety and efficacy of an intracerebral therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov/ct2/show/NCT03300453), with a recombinant AAV serotype 2/5 (rAAV2/5) coding human NAGLU in four children with MPS IIIB syndrome receiving immunosuppression. It was reported that AAV-mediated gene therapies might elicit a strong host immune response resulting in decreased transgene expression. To address this issue, we performed a comprehensive analysis of cellular immunity and cytokine patterns generated against the therapeutic enzyme in the four treated children over 5.5 years of follow-up. We report the emergence of memory and polyfunctional CD4+ and CD8+ T lymphocytes sensitized to the transgene soon after the start of therapy, and appearing in peripheral blood in waves throughout the follow-up. However, this response had no apparent impact on CNS transgene expression, which remained stable 66 months after surgery, possibly a consequence of the long-term immunosuppressive treatment. We also report that gene therapy did not trigger neuroinflammation, evaluated through the expression of cytokines and chemokines in patients' CSF. Milder disease progression in the youngest patient was found associated with low level and less differentiated circulating NAGLU-specific T cells, together with the lack of proinflammatory cytokines in the CSF. Findings in this study support a systematic and comprehensive immunomonitoring approach for understanding the impact immune reactions might have on treatment safety and efficacy of gene therapies.

Published
2021
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6. CD4+CD8+ T-Lymphocytes in Xenogeneic and Human Graft-versus-Host Disease

Author

Kutaiba Alhaj Hussen, David Michonneau, Vincent Biajoux, Seydou Keita, Laetitia Dubouchet, Elisabeth Nelson, Niclas Setterblad, Helene Le Buanec, Jean-David Bouaziz, Fabien Guimiot, Gérard Socié, Bruno Canque, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service d'Hématologie biologique [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gestionnaire, Hal Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université Paris Cité (UPCité)

Subjects
lcsh:Immunologic diseases. Allergy, CD3, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, MESH: Graft vs Host Disease, Hematopoietic stem cell transplantation, xenograft mouse model, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, graft-versus-host disease, Cytotoxic T cell, Immunology and Allergy, MESH: Animals, allogeneic hematopoietic stem cell transplantation, MESH: Mice, SCID, immunoregulatory diversion, MESH: Mice, MESH: Transplantation, Heterologous, MESH: Hematopoietic Stem Cell Transplantation, 030304 developmental biology, CD4 + CD8 + T lymphocytes, 0303 health sciences, MESH: Cytokines, MESH: Humans, biology, MESH: CD4-Positive T-Lymphocytes, MESH: Programmed Cell Death 1 Receptor, medicine.disease, MESH: CD8-Positive T-Lymphocytes, MESH: Male, 3. Good health, [SDV] Life Sciences [q-bio], CTL, Graft-versus-host disease, surgical procedures, operative, CD4+CD8+ T lymphocytes, biology.protein, MESH: Immunologic Memory, lcsh:RC581-607, MESH: T-Lymphocytes, Cytotoxic, MESH: Female, CD8, 030215 immunology
Abstract

Mechanisms driving acute graft-versus-host disease (aGVHD) onset in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are still poorly understood. To provide a detailed characterization of tissue-infiltrating T lymphocytes (TL) and search for eventual site-specific specificities, we developed a xenogeneic model of aGVHD in immunodeficient mice. Phenotypic characterization of xenoreactive T lymphocytes (TL) in diseased mice disclosed a massive infiltration of GVHD target organs by an original CD4+CD8+ TL subset. Immunophenotypic and transcriptional profiling shows that CD4+CD8+ TL comprise a major PD1+CD62L−/+ transitional memory subset (>60%) characterized by low level expression of cytotoxicity-related transcripts. CD4+CD8+ TL produce high IL-10 and IL-13 levels, and low IL-2 and IFN-γ, suggestive of regulatory function. In vivo tracking of genetically labeled CD4+ or CD8+ TL subsequently found that CD4+CD8+ TL mainly originate from chronically activated cytotoxic TL (CTL). On the other hand, phenotypic profiling of CD3+ TL from blood, duodenum or rectal mucosa in a cohort of allo-HSCT patients failed to disclose abnormal expansion of CD4+CD8+ TL independent of aGVHD development. Collectively, our results show that acquisition of surface CD4 by xenoreactive CD8+ CTL is associated with functional diversion toward a regulatory phenotype, but rule out a central role of this subset in the pathogenesis of aGVHD in allo-HSCT patients.

Published
2020
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7. Potent human broadly neutralizing antibodies to hepatitis B virus from natural controllers

Author

Camille Sureau, Verena Hehle, Oriane Fiquet, Cyril Planchais, Valérie Lorin, Marie-Louise Michel, Jordan D. Dimitrov, Helene Strick-Marchand, Nadege Pelletier, Stanislas Pol, Maxime Beretta, Hugo Mouquet, Thierry Hieu, Malika Ait-Goughoulte, James P. Di Santo, Andrea Stauffer, Marie-Noëlle Ungeheuer, Maryline Bourgine, Benjamin Vesin, Solen Morisse, BOURGINE, Maryline, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Human Antibody Responses to Viruses - HUMANTIVIRUSES - - EC:FP7:ERC2014-01-01 - 2018-12-31 - 337146 - VALID, Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, Institut Pasteur [Paris] (IP), F. Hoffmann-La Roche [Basel], Immunité Innée - Innate Immunity, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Centre de Recherche Translationnelle - Center for Translational Science (CRT), H. Mouquet received core grants from the G5 Institut Pasteur Program, the Milieu Intérieur Program (ANR-10-LABX-69-01) and INSERM. This work was funded by Institut Roche. V. Hehle and M. Beretta were supported by postdoctoral fellowships from Roche. V. Hehle and T. Hieu were also supported by the European Research Council–Seventh Framework Program (ERC-2013-StG 337146). H. Strick-Marchand was supported by the Institut Pasteur and Agence Nationale de Recherches sur le Sida et les Hépatites Virales (2016-16365, 2019-19241)., We are grateful to members of the Center for Translational Sciences (Institut Pasteur), Cassandre Von Platen (Clinical core) for the preparation of the RAPIVIB protocol, and Gloria Morizot (Investigation Clinique et Accès aux Ressources Biologiques) for collecting biological samples and associated personal data. We also thank Sandrine Schmutz, Sophie Novault (UTechS CB, Center for Translational Sciences, Institut Pasteur), and Ayrin Kök for their technical help with single cell sorting, and Dr. J. Aguilar (Center for Genetic Engineering and Biotechnology, Havana, Cuba) for providing us with the purified adw HBsAg particles., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), European Project: 337146,EC:FP7:ERC,ERC-2013-StG,HUMANTIVIRUSES(2014), École Pratique des Hautes Études (EPHE), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP)

Subjects
0301 basic medicine, HBsAg, MESH: Epitopes, MESH: Hepatitis B, Chronic, Immunology, MESH: Flow Cytometry, Viremia, medicine.disease_cause, Epitope, Virus, MESH: Antibodies, Neutralizing, MESH: Cross Reactions, 03 medical and health sciences, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, 0302 clinical medicine, MESH: B-Lymphocytes, medicine, Immunology and Allergy, MESH: Animals, MESH: Mice, Hepatitis B virus, MESH: Hepatitis B Vaccines, MESH: Humans, MESH: Hepatitis B, biology, MESH: Neutralization Tests, MESH: Enzyme-Linked Immunosorbent Assay, virus diseases, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Hepatitis B, medicine.disease, Virology, digestive system diseases, MESH: Hepatitis B Surface Antigens, 3. Good health, Vaccination, MESH: Hepatitis B virus, 030104 developmental biology, MESH: Immunologic Memory, biology.protein, 030211 gastroenterology & hepatology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Antibody
Abstract

International audience; Rare individuals can naturally clear chronic hepatitis B virus (HBV) infection and acquire protection from reinfection as conferred by vaccination. To examine the protective humoral response against HBV, we cloned and characterized human antibodies specific to the viral surface glycoproteins (HBsAg) from memory B cells of HBV vaccinees and controllers. We found that human HBV antibodies are encoded by a diverse set of immunoglobulin genes and recognize various conformational HBsAg epitopes. Strikingly, HBsAg-specific memory B cells from natural controllers mainly produced neutralizing antibodies able to cross-react with several viral genotypes. Furthermore, monotherapy with the potent broadly neutralizing antibody Bc1.187 suppressed viremia in vivo in HBV mouse models and led to post-therapy control of the infection in a fraction of animals. Thus, human neutralizing HBsAg antibodies appear to play a key role in the spontaneous control of HBV and represent promising immunotherapeutic tools for achieving HBV functional cure in chronically infected humans.

Published
2020
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8. Fungal mediated innate immune memory, what have we learned?

Author

Jessica Quintin, Immunologie des Infections fongiques - immunology of fungal infections, Institut Pasteur [Paris], Institut Carnot Pasteur Maladie Infectieuse ANR-11-CARN-017-01, This work was supported by the ANR JCJC grant [ANR-16-CE15-0014-01] and the Institut Carnot Pasteur MI grant [ANR 11-CARN 017-01] (to J.Q.)., ANR-16-CE15-0014,IIMory,Mémoire immunologique innée des défenses de l'hôte(2016), and Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, animal diseases, [SDV]Life Sciences [q-bio], Context (language use), chemical and pharmacologic phenomena, β-glucan, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Fungal Components, Immunological memory, MESH: Monocytes, Monocytes, 03 medical and health sciences, Innate immune memory, 0302 clinical medicine, MESH: Mycoses, Immunity, Candida albicans, Humans, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Immune status, Innate immune system, MESH: Humans, biology, Macrophages, MESH: Candida albicans, Fungi, MESH: Macrophages, Cell Biology, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Immunity, Innate, 3. Good health, 030104 developmental biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Mycoses, Immunology, MESH: Immunologic Memory, bacteria, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Immunity, Innate, Immunologic Memory, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; The binary classification of mammalian immune memory is now obsolete. Innate immune cells carry memory characteristics. The overall capacity of innate immune cells to remember and alter their responses is referred as innate immune memory and the induction of a non-specific memory resulting in an enhanced immune status is termed "trained immunity". Historically, trained immunity was first described as triggered by the human fungal pathogen Candida albicans. Since, numerous studies have accumulated and deciphered the main characteristics of trained immunity mediated by fungi and fungal components. This review aims at presenting the newly described aspect of memory in innate immunity with an emphasis on the historically fungal mediated one, covering the known molecular mechanisms associated with training. In addition, the review uncovers the numerous non-specific effect that β-glucans trigger in the context of infectious diseases and septicaemia, inflammatory diseases and cancer.

Published
2019
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9. A Seroepidemiological Study of Serogroup A Meningococcal Infection in the African Meningitis Belt

Author

Manigart, Olivier, Trotter, Caroline, Findlow, Helen, Assefa, Abraham, Mihret, Wude, Moti Demisse, Tesfaye, Yeshitela, Biruk, Osei, Isaac, Hodgson, Abraham, Quaye, Stephen Laryea, Sow, Samba, Coulibaly, Mamadou, Diallo, Kanny, Traore, Awa, Collard, Jean-Marc, Moustapha Boukary, Rahamatou, Djermakoye, Oumarou, Mahamane, Ali Elhaji, Jusot, Jean-François, Sokhna, Cheikh, Alavo, Serge, Doucoure, Souleymane, Ba, El Hadj, Dieng, Mariétou, Diallo, Aldiouma, Daugla, Doumagoum Moto, Omotara, Babatunji, Chandramohan, Daniel, Hassan-King, Musa, Nascimento, Maria, Woukeu, Arouna, Borrow, Ray, Stuart, James M, Greenwood, Brian, London School of Hygiene and Tropical Medicine (LSHTM), Medical Research Council Unit The Gambia (MRC), University of Cambridge [UK] (CAM), Public Health England North West [Manchester] (PHE), Public Health England [London], Armauer Hansen Research Institute (AHRI), Navrongo Health Research Centre [Navrongo, Ghana] (NHRC), Centre pour les Vaccins en Développement [Bamako] (CVD), Centre de Recherche Médicale et Sanitaire (Niamey, Niger) (CERMES), Réseau International des Instituts Pasteur (RIIP), Institut de recherche pour le développement (IRD [Sénégal]), Centre de Support en Santé Internationale [N'Djamena, Tchad] (CSSI), University of Maiduguri, This work was supported by Wellcome Trust (grant no. 086546/Z/08/Z), www.wellcome.ac.uk, Bill & Melinda Gates Foundation (grant no. 51251), www.gatesfoundation.org., Trotter, Caroline [0000-0003-4000-2708], and Apollo - University of Cambridge Repository

Subjects
Male, Bacterial Diseases, Physiology, lcsh:Medicine, Meningococcal Disease, Neisseria meningitidis, MESH: Africa, Biochemistry, Ghana, MESH: Meningococcal Vaccines, Geographical Locations, Seroepidemiologic Studies, Infectious Diseases of the Nervous System, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immune Physiology, MESH: Child, MESH: Antibodies, Bacterial, Medicine and Health Sciences, Public and Occupational Health, Enzyme-Linked Immunoassays, lcsh:Science, Child, MESH: Aged, MESH: Immunoglobulin G, Immune System Proteins, MESH: Middle Aged, Vaccination, MESH: Meningitis, Meningococcal, MESH: Enzyme-Linked Immunosorbent Assay, Middle Aged, Antibodies, Bacterial, Vaccination and Immunization, MESH: Infant, Senegal, Infectious Diseases, Neurology, Child, Preschool, Carrier State, MESH: Immunologic Memory, Female, MESH: Carrier State, Research Article, Adult, Adolescent, Inflammatory Diseases, Immunology, Enzyme-Linked Immunosorbent Assay, Meningococcal Vaccines, Meningitis, Meningococcal, Serogroup, Research and Analysis Methods, Antibodies, MESH: Neisseria meningitidis, MESH: Cross-Sectional Studies, Humans, Meningitis, Epidemics, Immunoassays, MESH: Epidemics, Aged, MESH: Adolescent, MESH: Seroepidemiologic Studies, MESH: Humans, lcsh:R, MESH: Child, Preschool, Infant, Biology and Life Sciences, Proteins, MESH: Adult, MESH: Serogroup, MESH: Vaccination, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Male, Cross-Sectional Studies, Immunoglobulin G, People and Places, Africa, Immunologic Techniques, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Ethiopia, Preventive Medicine, Immunologic Memory, MESH: Female
Abstract

International audience; The pattern of epidemic meningococcal disease in the African meningitis belt may be influenced by the background level of population immunity but this has been measured infrequently. A standardised enzyme-linked immunosorbent assay (ELISA) for measuring meningococcal serogroup A IgG antibodies was established at five centres within the meningitis belt. Antibody concentrations were then measured in 3930 individuals stratified by age and residence from six countries. Seroprevalence by age was used in a catalytic model to determine the force of infection. Meningococcal serogroup A IgG antibody concentrations were high in each country but showed heterogeneity across the meningitis belt. The geometric mean concentration (GMC) was highest in Ghana (9.09 μg/mL [95% CI 8.29, 9.97]) and lowest in Ethiopia (1.43 μg/mL [95% CI 1.31, 1.57]) on the margins of the belt. The force of infection was lowest in Ethiopia (λ = 0.028). Variables associated with a concentration above the putative protective level of 2 μg/mL were age, urban residence and a history of recent vaccination with a meningococcal vaccine. Prior to vaccination with the serogroup A meningococcal conjugate vaccine, meningococcal serogroup A IgG antibody concentrations were high across the African meningitis belt and yet the region remained susceptible to epidemics.

Published
2016
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10. IL-2 and IL-15 regulate CD8+ memory T-cell differentiation but are dispensable for protective recall responses

Author

Mathieu, Cédric, Beltra, Jean-Christophe, Charpentier, Tania, Bourbonnais, Sara, Di Santo, James P, Lamarre, Alain, Decaluwe, Hélène, Research Center, CHU Sainte-Justine, Universite de Montreal, Montreal, Quebec, Canada, Centre de recherche de l'hôpital Sainte Justine, CHU Sainte Justine [Montréal]-CHU Sainte Justine [Montréal], University of Montréal, University of Montreal, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Immunité Innée - Innate Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Funded by - Canadian Institutes of Health Research. Grant Number: CIHR MOP-130469 - Institut Pasteur and the INSERM, Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Interleukin-15, MESH: Cell Differentiation, IL-2, [SDV]Life Sciences [q-bio], MESH: Interleukin-15, Cell Differentiation, T-cell differentiation, MESH: Interleukin-2, CD8-Positive T-Lymphocytes, CD8+ T cells, MESH: CD8-Positive T-Lymphocytes, Interleukin-2 Receptor beta Subunit, Mice, Inbred C57BL, MESH: Interleukin-2 Receptor beta Subunit, Mice, IL-15, Memory, MESH: Mice, Inbred C57BL, MESH: Immunologic Memory, Animals, Interleukin-2, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Animals, Immunologic Memory, MESH: Mice
Abstract

International audience; The ability to mount effective secondary responses is a cardinal feature of memory CD8(+) T cells. An understanding of the factors that regulate the generation and recall capacities of memory T cells remains to be ascertained. Several cues indicate that two highly related cytokines, IL-2 and IL-15, share redundant functions in this process. To establish their combined roles in memory CD8(+) T-cell development, maintenance, and secondary responses, we compared the outcome of adoptively transferred IL2Rβ(+/-) or IL2Rβ(-/-) CD8(+) T cells after an acute viral infection in mice. Our results demonstrate that both IL-2 and IL-15 signals condition the differentiation of primary and secondary short-lived effector cells by altering the transcriptional network governing lineage choices. These two cytokines also regulate the homeostasis of the memory T-cell pool, with effector memory CD8(+) T cells being the most sensitive to these two interleukins. Noticeably, the inability to respond to both cytokines limits the proliferation and survival of primary and secondary effectors cells, whereas it does not preclude potent cytotoxic functions and viral control either initially or upon rechallenge. Globally, these results indicate that lack of IL-2 and IL-15 signaling modulates the CD8(+) T-cell differentiation program but does not impede adequate effector functions.

Published
2015
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11. Mucosal-associated invariant T cell–rich congenic mouse strain allows functional evaluation

Author

Lionel Le Bourhis, Olivier Lantz, Yue Cui, Katarzyna Franciszkiewicz, Yvonne K. Mburu, Sylvie Rabot, Alexandra Kachaner, Emmanuel Martin, Claire Soudais, Stanislas Mondot, Virginie Premel, Livine Duban, Jean Jaubert, Molly A. Ingersoll, Jean-Pierre de Villartay, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Génétique Fonctionnelle de la Souris, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biopathologie, Institut Curie [Paris], This work was supported by grants from INSERM, Agence Nationale de la Recherche (ANR), DIM Ile de France, Association pour la Recherche sur la Sclérose En Plaques (ARSEP), Institut Mérieux, and Institut Curie. Y.K. Mburu is a recipient of the Lloyd J. Old Memorial Award and is supported by an Irvington Institute postdoctoral fellowship from the Cancer Research Institute., Vougny, Marie-Christine, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Curie

Subjects
MESH: Minor Histocompatibility Antigens, MESH: Nuclear Receptor Subfamily 1, Group F, Member 3, Receptors, Antigen, T-Cell, alpha-beta, MESH: Chemotaxis, Leukocyte, MESH: Urinary Tract Infections, Lymphocyte Activation, MESH: Mice, Knockout, MESH: Histocompatibility Antigens Class I, MESH: Promyelocytic Leukemia Zinc Finger Protein, Mice, 0302 clinical medicine, Promyelocytic Leukemia Zinc Finger Protein, MESH: Animals, Mice, Knockout, 0303 health sciences, education.field_of_study, Lymphokines, MESH: Receptors, Antigen, T-Cell, alpha-beta, Microbiota, MESH: Polymorphism, Single Nucleotide, General Medicine, Nuclear Receptor Subfamily 1, Group F, Member 3, Natural killer T cell, MESH: Crosses, Genetic, Chemotaxis, Leukocyte, medicine.anatomical_structure, Phenotype, Radiation Chimera, Urinary Tract Infections, MESH: Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor, MESH: Immunologic Memory, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Kruppel-Like Transcription Factors, Research Article, MESH: Lymphocyte Count, [SDV.IMM] Life Sciences [q-bio]/Immunology, Lymphoid Tissue, MESH: Radiation Chimera, MESH: Mice, Transgenic, T cell, Population, Congenic, Kruppel-Like Transcription Factors, Mice, Transgenic, Mucosal associated invariant T cell, Biology, MESH: Phenotype, Polymorphism, Single Nucleotide, Minor Histocompatibility Antigens, 03 medical and health sciences, Mice, Congenic, MESH: Mice, Congenic, MESH: Mice, Inbred C57BL, MESH: Germ-Free Life, medicine, Animals, Germ-Free Life, Humans, MESH: Microbiota, Lymphocyte Count, Receptors, Cytokine, education, MESH: Lymphocyte Activation, MESH: Mice, Crosses, Genetic, 030304 developmental biology, MESH: Humans, MESH: Lymphokines, T-cell receptor, Histocompatibility Antigens Class I, Laboratory mouse, Gene rearrangement, Molecular biology, MESH: Receptors, Cytokine, Mice, Inbred C57BL, Disease Models, Animal, MESH: Natural Killer T-Cells, MESH: Lymphoid Tissue, Natural Killer T-Cells, MESH: Disease Models, Animal, Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor, Immunologic Memory, MESH: Female, 030215 immunology
Abstract

Mucosal-associated invariant T cells (MAITs) have potent antimicrobial activity and are abundant in humans (5%-10% in blood). Despite strong evolutionary conservation of the invariant TCR-alpha chain and restricting molecule MR1, this population is rare in laboratory mouse strains (approximate to 0.1% in lymphoid organs), and lack of an appropriate mouse model has hampered the study of MAIT biology. Herein, we show that MAITs are 20 times more frequent in clean wild-derived inbred CAST/EiJ mice than in C57BL/6J mice. Increased MAIT frequency was linked to one CAST genetic trait that mapped to the TCR-alpha locus and led to higher usage of the distal V alpha segments, including V alpha 19. We generated a MAIT(hl) congenic strain that was then crossed to a transgenic Rorcgt-GFP reporter strain. Using this tool, we characterized polyclonal mouse MAITs as memory (CD44(+)) CD4(-)CD8(lo/neg) T cells with tissue-homing properties (CCR6*CCR7(-)). Similar to human MAITs, mouse MAITs expressed the cytokine receptors IL-7R, IL-18R alpha, and IL-12R beta and the transcription factors promyelocytic leukemia zinc finger (PLZF) and RAR-related orphan receptory gamma (R0R gamma t). Mouse MAITs produced Th1/2/17 cytokines upon TCR stimulation and recognized a bacterial compound in an MR1-dependent manner. During experimental urinary tract infection, MAITs migrated to the bladder and decreased bacterial load. Our study demonstrates that the MAIT(hi) congenic strain allows phenotypic and functional characterization of naturally occurring mouse MAITs in health and disease.

Published
2015
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