title: A novel immunoregulatory role for NK-cell cytotoxicity in protection from HLH-like immunopathology in mice.
abstract: 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.
authors.affiliation: Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM Unité Mixte de Recherche 1163, Paris France; Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris France;
authors.forename: Fernando E
authors.initials: FE
authors.lastname: Sepulveda
authors.affiliation: Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM Unité Mixte de Recherche 1163, Paris France; Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris France;
authors.forename: Sophia
authors.initials: S
authors.lastname: Maschalidi
authors.affiliation: Département d'Immunologie, Institut Pasteur, Unité d'Immunité Innée, Paris, France; Institut Pasteur, INSERM U668, Paris, France;
authors.forename: Christian A J
authors.initials: CA
authors.lastname: Vosshenrich
authors.affiliation: Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM Unité Mixte de Recherche 1163, Paris France; Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris France;
authors.forename: Alexandrine
authors.initials: A
authors.lastname: Garrigue
authors.affiliation: Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM Unité Mixte de Recherche 1163, Paris France; Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris France;
authors.forename: Mathieu
authors.initials: M
authors.lastname: Kurowska
authors.affiliation: Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM Unité Mixte de Recherche 1163, Paris France; Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris France;
authors.forename: Gael
authors.initials: G
authors.lastname: Ménasche
authors.affiliation: Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM Unité Mixte de Recherche 1163, Paris France; Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris France; Immunology and Pediatric Hematology Department, Necker Children's Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France; Collège de France, Paris, France; and.
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Département d'Immunologie, Institut Pasteur, Unité d'Immunité Innée, Paris, France; Institut Pasteur, INSERM U668, Paris, France;
authors.forename: James P
authors.initials: JP
authors.lastname: Di Santo
authors.affiliation: Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM Unité Mixte de Recherche 1163, Paris France; Imagine Institute, Paris Descartes University-Sorbonne Paris Cité, Paris France; Centre d'Etudes des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000276:immunology* / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology / Q000473:pathology / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019562:Viral Load
chemical_list: D007371:Interferon-gamma