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.

Type I IFN has both direct and indirect effects on NK cell development and maturation (Mizutani et al., 2012; Guan et al., 2014) . In accordance with these prior studies, resting splenic NK cells from Ifnar −/− mice exhibited an increase in immature NK cells as indicated by CD27, CD11b, and KLRG1 expression when compared with WT (unpublished data). Thus, we generated mixed WT :Ifnar − /− bone marrow chimeras in which development of Ifnar −/− NK cells appeared grossly normal (unpublished data) and investigated the role of type I IFNs on the NK cell response against MCMV infection. At day 1.5 after MCMV infection, Ifnar −/− NK cells in mixed chimeric mice exhibited defective up-regulation of CD69 (Fig. 3 A) , a marker of activation downstream of type I IFN signaling (Gerosa et al., 1991) . Ifnar −/− NK cells also failed to up-regulate granzyme B compared with their WT counterparts at day 1.5 PI (Fig. 3 B) , consistent with a previous study (Baranek et al., 2012) . Interestingly, Ifnar −/− NK cells produced more IFN-γ than WT NK cells at day 1.5 PI (Fig. 3 B) . STAT1 phosphorylation was completely ablated in NK cells that cannot sense type I IFNs (Fig. 3 C) . These findings demonstrate the ability of type I IFNs to directly impact the expression of key effector molecules in NK cells, likely via robust STAT1 phosphorylation.