Journal
BLOOD
Volume 125, Issue 9, Pages 1427-1434Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-09-602946
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Funding
- Association pour la Recherche sur le Cancer
- Becas Chile
- Imagine Foundation
- French National Institutes of Health and Medical Research (INSERM)
- Agence National de la Recherche [HLH-Cytotox/ANR-12-BSV1-0020-01]
- ARC Foundation [PJA 2013120047]
- European Research Council (PIDImmun) [249816]
- European Research Council (ERC) [249816] Funding Source: European Research Council (ERC)
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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.
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