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.

To evaluate the contribution of NKG2D triggering in NK cell fratricide, equal numbers of WT and Ifnar −/− NK cells were cotransferred into WT hosts that received a nondepleting neutralizing anti-NKG2D-blocking antibody (or PBS as a negative control) and then were infected with LCMV. As expected, WT NK cells preferentially survived compared with Ifnar −/− NK cells in the PBS-treated control mice (Fig. 5 C) . However, in mice receiving anti-NKG2D, a similar persistence between WT and Ifnar −/− NK cells was observed (Fig. 5 C) , suggesting that the NKG2D pathway may represent at least one mechanism that activates fratricide. Similar results were observed in mice infected with MCMV lacking m157 (not depicted). Furthermore, we confirmed the expression of NKG2D ligands on the NK cells soon after infection. After LCMV infection of WT :Ifnar − /− bone marrow chimeras, Ifnar −/− NK cells expressed significantly higher amounts of NKG2D ligand (Fig. 5 D) . This finding suggests that type I IFN may have a direct role in suppressing NKG2D ligand induction during viral infection. Collectively, these data indicate that type I IFN acts to combat NK cell-mediated fratricide that is dependent on NKG2D triggering and perforin release.