Contributors: 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 (IP)-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)-Hôpital Necker - Enfants Malades AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Collège de France - 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,ERC-2009-AdG,ERC-2009-AdG,PIDIMMUN(2010)
نبذة مختصرة : 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.
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