A novel immunoregulatory role for NK-cell cytotoxicity in protection from HLH-like immunopathology in mice.

Fernando E Sepulveda (1, 2) , Sophia Maschalidi (2, 1) , Christian A. J. Vosshenrich (3) , Alexandrine Garrigue (2, 1) , Mathieu Kurowska (2, 1) , Gaël Ménasche (2, 1) , Alain Fischer (2, 4, 1, 5) , James P Di Santo (3) , Geneviève de Saint Basile (2, 6, 1)

1 Laboratory of Normal and Pathological Homeostasis of the Immune System
2 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
3 Immunité Innée
4 Service d'immuno-hématologie pédiatrique [CHU Necker]
5 Collège de France - Chaire Médecine expérimentale (A. Fischer)
6 Centre d'étude des Déficits Immunitaires

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.

Domains: Life Sciences [q-bio]; Immunology; Innate immunity

Fernando E Sepulveda, Sophia Maschalidi, Christian A. J. Vosshenrich, Alexandrine Garrigue, Mathieu Kurowska, et al.. A novel immunoregulatory role for NK-cell cytotoxicity in protection from HLH-like immunopathology in mice.. Blood, 2015, 125 (9), pp.1427-34. ⟨10.1182/blood-2014-09-602946⟩. ⟨pasteur-01489214⟩