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.

Although substantial amounts of type I IFN are produced during viral infection, this cytokine is constitutively present at basal levels and affects the development and homeostasis of various hematopoietic lineages (Honda et al., 2004; Sato et al., 2009; Gough et al., 2012 ). An indirect effect of type I IFN on NK cell development and maturation has been described recently (Mizutani et al., 2012; Guan et al., 2014) . Because the prolific expansion and generation of memory NK cells during mouse cytomegalovirus (MCMV) infection are dependent predominantly on the proinflammatory cytokines IL-12 and IL-18 (Andoniou et al., 2005; Sun et al., 2012; Madera and Sun, 2015) , it was of interest to determine whether type I IFNs play a role in these processes. Here, we use NK cells deficient in the IFN AR1 chain (Ifnar −/− ) in an adoptive cotransfer system and mixed bone marrow chimeric mice to investigate the direct influence of type I IFN signaling on NK cells responding against MCMV infection. cells were able to mature nearly as well as WT NK cells in response to MCMV infection, as indicated by the down-regulation of CD27 and up-regulation of CD11b and KLRG1 (Fig. 1 , B and C). We also investigated the contribution of type I IFN signaling in NK cells for protection against lethal MCMV challenge. Equal numbers of naive WT or Ifnar −/− NK cells were transferred into separate neonatal mice and then challenged with MCMV. In contrast to mice receiving WT NK cells, which protected ∼50% of recipients, all mice receiving Ifnar −/− NK cells succumbed to infection by day 15 postinfection (PI; Fig. 1 D) , highlighting the importance of type I IFN signaling, specifically in NK cells, for protective immunity against viral challenge.