• R Orhan and J-M Cavaillon.
• L'Oréal Research Scholarship, Unit Cytokines & Inflammation, Paris, France.
• Shock. 2015 Oct 1;44 Suppl 2:10.

IntroductionSepsis is a life threatening condition but its toll on human health extends way beyond the acute episode. Sepsis induced immune dysfunction has been suggested to be responsible for susceptibility to opportunistic infection, viral reactivation and reduced lifespan in sepsis survivors.MethodsWe have explored the ex-vivo response of splenic natural killer (NK) cells in mice surviving endotoxinemia.ResultsWe found that early on, 24 hours after LPS administration, NK reactivity to both LPS or cytokine cocktails (IL-12 + IL-18 or IL-15) was completely abolished in terms of IFNγ production. We observed that the diminished reactivity of NKs to LPS persisted till 7 and even 14 days after endotoxinemia, and was accompanied by transient changes in NK phenotype (CD69, CD11c) and a shift of the cytokine profile from IFNγ to IFNγ and IL-10. At these moments, cytokine levels in culture supernatants revealed that TNF production by LPS-activated whole spleen cells, was unaffected, excluding classical endotoxin tolerance and IL-6 production was heightened suggesting a different kind of response. Endotoxinemia survivor mice showed increased survival and reduced weight loss following a second challenge with a lethal dose of LPS at 10 days after the first one.ConclusionThese results suggest that in addition to the short lasting endotoxin tolerance phenomenon observed with monocytes/macrophages following a first LPS encounter, another long lasting process exists at the NK cell levels, associated with a functional reprogramming. Thus, the modified immune status of NK cells long after a first LPS encounter was associated with an enhanced resistance.

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