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.

Recently, type I IFN has been shown to protect antiviral CD8 + T cells from NK cell-mediated killing, as two independent studies observed the selective elimination of Ifnar −/− CD8 + T cells after LCMV infection (Crouse et al., 2014; Xu et al., 2014) . This preferential elimination of Ifnar −/− CD8 + T cells was a consequence of the differential expression of inhibitory (MHC class I; Xu et al., 2014) and activating (NKp46; Crouse et al., 2014) NK cell signals. We explored the contribution of these distinct pathways in NK-NK cell fratricide and found that Ifnar −/− NK cells exhibited a modest reduction (15-30%) in MHC class I expression after MCMV infection when compared with WT NK cells (unpublished data). However, NK cells are known to tolerate target cells that express a wide range of MHC class I surface levels (Jonsson et al., 2010; unpublished data) , with rejection only occurring when target cell MHC class I expression falls below 20% of the host levels (i.e., an 80% reduction in MHC class I expression; Brodin et al., 2010) . Thus, a 30% decrease in MHC class I expression will unlikely result in missing self-recognition and killing. However, because the triggering of NK cell activation and cytotoxicity stems from the net balance of activating and inhibitory input signals (Joncker et al., 2009 ), a modest decrease in MHC class I expression compounded by a strong activating signal, like that provided by NKG2D ligands, could possibly contribute to the selective killing of Ifnar −/− NK cells observed in our study. Expression of NKp46 ligands was another mechanism suggested to trigger NK cell-mediated killing of Ifnar −/− CD8 + T cells (Crouse et al., 2014) ; however, we found no role for NKp46 in NK cell-mediated elimination of Ifnar −/− NK cells. Thus, unlike with NK cellmediated killing of CD8 + T cells, our data do not support a role for MHC class I molecules or NKp46 ligands in NK-NK cell fratricide during viral infection.