A novel immunoregulatory role for NK-cell cytotoxicity in protection from HLH-like immunopathology in mice
| Autor: | James P. Di Santo, Sophia Maschalidi, Fernando E. Sepulveda, Geneviève de Saint Basile, Gaël Ménasché, Alain Fischer, Christian A. J. Vosshenrich, Mathieu Kurowska, Alexandrine Garrigue |
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| Přispěvatelé: | Laboratory of Normal and Pathological Homeostasis of the Immune System, Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité Innée, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie 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), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Centre d'étude des Déficits Immunitaires, This work was supported by fellowships from the Association pour la Recherche sur le Cancer and Becas Chile (F.E.S.) and by fellowships from the Association pour la Recherche sur le Cancer and the Imagine Foundation (S.M.). This work was also supported by the French National Institutes of Health and Medical Research (INSERM), the Agence National de la Recherche (HLH-Cytotox/ANR-12-BSV1-0020-01), the ARC Foundation (grant PJA 2013120047), the European Research Council (PIDImmun, advanced grant 249816), and the Imagine Foundation., ANR-12-BSV1-0020,HLH-cytotox,Bases moléculaires et physiopathologie des syndromes hémophagocytaires(2012), European Project: 249816,EC:FP7:ERC,ERC-2009-AdG,PIDIMMUN(2010), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Médecine expérimentale (A. Fischer), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Developpement Normal et Pathologique du Système Immunitaire, Martin, Marie, BLANC - Bases moléculaires et physiopathologie des syndromes hémophagocytaires - - HLH-cytotox2012 - ANR-12-BSV1-0020 - BLANC - VALID, Primary immunodeficiency diseases as models for the study of the immune system - PIDIMMUN - - EC:FP7:ERC2010-07-01 - 2015-06-30 - 249816 - VALID |
| Rok vydání: | 2015 |
| Předmět: |
Cytotoxicity
Immunologic [SDV]Life Sciences [q-bio] [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity Biochemistry MESH: Spleen/virology Pathogenesis Mice MESH: Lymphocytic Choriomeningitis/immunology 0302 clinical medicine MESH: Killer Cells Natural/virology hemic and lymphatic diseases Immunopathology Lymphocytic choriomeningitis virus Cytotoxic T cell MESH: Animals Cytotoxicity Cells Cultured MESH: Cytotoxicity Immunologic/immunology MESH: Interferon-gamma/secretion MESH: Lymphohistiocytosis Hemophagocytic/pathology 0303 health sciences Hematology Viral Load 3. Good health Killer Cells Natural MESH: Spleen/immunology MESH: Lymphocytic choriomeningitis virus/immunology [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology MESH: T-Lymphocytes Cytotoxic/immunology MESH: Lymphocytic Choriomeningitis/pathology [SDV.IMM]Life Sciences [q-bio]/Immunology MESH: Viral Load MESH: Cells Cultured endocrine system MESH: Lymphohistiocytosis Hemophagocytic/immunology Immunology chemical and pharmacologic phenomena MESH: Lymphocytic Choriomeningitis/virology Lymphocytic Choriomeningitis Biology MESH: Killer Cells Natural/pathology Lymphocytic choriomeningitis Lymphohistiocytosis Hemophagocytic Virus Interferon-gamma 03 medical and health sciences MESH: Lymphohistiocytosis Hemophagocytic/virology MESH: Mice Inbred C57BL MESH: Cell Proliferation medicine Animals [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity MESH: Mice Cell Proliferation 030304 developmental biology Cell Biology medicine.disease Mice Inbred C57BL CTL MESH: Killer Cells Natural/immunology Immune disorder Spleen [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology MESH: Spleen/pathology T-Lymphocytes Cytotoxic 030215 immunology |
| Zdroj: | Blood Blood, American Society of Hematology, 2015, 125 (9), pp.1427-34. ⟨10.1182/blood-2014-09-602946⟩ Blood, 2015, 125 (9), pp.1427-34. ⟨10.1182/blood-2014-09-602946⟩ Blood, American Society of Hematology, 2015, 125 (9), pp.1427-1434. ⟨10.1182/blood-2014-09-602946⟩ |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2014-09-602946 |
| Popis: | International audience; The impairment of cytotoxic activity of lymphocytes disturbs immune surveillance and leads to the development of hemophagocytic lymphohistiocytic syndrome (HLH). Although cytotoxic T lymphocyte (CTL) control of HLH development is well documented, the role for natural killer (NK)-cell effector functions in the pathogenesis of this immune disorder remains unclear. In this study, we specifically targeted a defect in cytotoxicity to either CTL or NK cells in mice so as to dissect the contribution of these lymphocyte subsets to HLH-like disease severity after lymphocytic choriomeningitis virus (LCMV) infection. We found that NK-cell cytotoxicity was sufficient to protect mice from the fatal outcome that characterizes HLH-like disease and was also sufficient to reduce HLH-like manifestations. Mechanistically, NK-cell cytotoxicity reduced tissue infiltration by inflammatory macrophages and downmodulated LCMV-specific T-cell responses by limiting hyperactivation of CTL. Interestingly, the critical protective effect of NK cells on HLH was independent of interferon-γ secretion and changes in viral load. Therefore our findings identify a crucial role of NK-cell cytotoxicity in limiting HLH-like immunopathology, highlighting the important role of NK cytotoxic activity in immune homeostasis. |
| Databáze: | OpenAIRE |
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