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.

Traditionally classified as a member of the innate immune system, NK cells are known to provide a crucial line of early defense against viral infections in both humans and mice (Bukowski et al., 1985; Rager-Zisman et al., 1987; Biron et al., 1989) . In more recent years, NK cells have been described to possess many features of adaptive immunity (Sun and Lanier, 2011; Vivier et al., 2011) . However, the molecular mechanisms behind these adaptive responses are not well understood. Our current findings demonstrate that direct type I IFN signaling in NK cells promotes their optimal activation and function during MCMV infection. In certain viral systems, such as during vaccinia virus infection, NK cell-dependent and -independent effects of type I IFN have been reported where NK cells were directly harvested from WT and Ifnar1 −/− or Stat1 −/− mice (Martinez et al., 2008; Fortin et al., 2013) . Other viral models, using mouse hepatitis virus or dengue virus infection, underscore the importance of type I IFN signaling in innate cells for viral control, with the primary focus being macrophages and dendritic cells (Cervantes-Barragán et al., 2009; Züst et al., 2014) . In the context of MCMV infection, type I IFN has long been known to mediate antiviral effects, partly through its activity on NK cells (Nguyen et al., 2002) . However, the overwhelming majority of previous studies have failed to distinguish between the direct and indirect effects of type I IFNs on NK cells during the course of MCMV infection. Extending a recent study reporting both direct and indirect effects of type I IFN on the early NK cell and dendritic cell response after MCMV infection (Baranek et al., 2012) , our current study demonstrates that type I IFN acts directly on NK cells to promote their longterm survival by protecting them from elimination via NK cell-mediated fratricide.