Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide

Madera, Sharline; Rapp, Moritz; Firth, Matthew A.; Beilke, Joshua N.; Lanier, Lewis L.; Sun, Joseph C.

Previous studies have found conflicting roles for type I IFN in the induction of NK cell proliferation after MCMV infection (Orange and Biron, 1996; Geurs et al., 2009 ). These studies relied on the direct infection of IFN-deficient mice (Geurs et al., 2009) , which fails to consider the effects of higher viral loads or administration of IFN-neutralizing antibodies during viral infection (Orange and Biron, 1996) , which could directly affect production of IL-15, a cytokine known to influence NK cell survival and proliferation. We demonstrate that NK cells unable to sense type I IFNs retain a functional proliferative program and even exhibit a modest increase in proliferation after infection when compared with WT NK cells (Figs. 4 A and 6 A) ; however, Ifnar −/− NK cells were found to undergo more apoptosis than WT NK cells (Fig. 4 B) . Although our findings suggest that a perforin-and NK-G2D-dependent fratricide mechanism plays a major role in the increased cell death observed in Ifnar −/− NK cells during viral infection, additional survival mechanisms may be lacking in these cells. Type I IFN previously has been described to promote the survival of activated CD8 + T cells in a manner that is independent of Bcl-2 (Marrack et al., 1999) , perhaps by enhancing the responsiveness of antigen-specific CD8 + T cells to IL-2 and IL-15 (Le Bon et al., 2006) and by regulating the expression of IL-7 and IL-15 cytokine receptors (Schluns and Lefrançois, 2003) . Consistent with this hypothesis, we found no difference in the expression of Bcl-2 between WT and Ifnar −/− NK cells after MCMV infection (unpublished data). Thus, a Bcl-2-independent mechanism is promoting survival of antigen-specific NK cells that can sense type I IFNs, shielding these cells from apoptosis. Future studies investigating gene targets of STAT1 may reveal additional prosurvival mechanisms in NK cells exposed to type I IFNs during viral infection.