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

作者：Sepulveda Fernando E^*; Maschalidi Sophia; Vosshenrich Christian A J; Garrigue Alexandrine; Kurowska Mathieu; Menasche Gael; Fischer Alain; Di Santo James P; de Saint Basile Genevieve

来源：Blood, 2015, 125(9): 1427-1434.

DOI：10.1182/blood-2014-09-602946

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-gamma 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.

• 出版日期2015-2-26