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.

If host NK cells are indeed mediating fratricide of transferred Ifnar −/− NK cells during viral infection, we hypothesized that Ifnar −/− NK cells should expand normally and generate long-lived memory after MCMV infection in a system devoid of NK cells. Equal numbers of Ly49H + WT (CD45.1) and Ifnar −/− (CD45.2) NK cells from mixed chimeric mice were transferred into Rag2 −/− × Il2rg −/− hosts (which lack T, B, and NK cells), and the recipient mice were then infected with MCMV. After MCMV infection, Ifnar −/− NK cells expanded robustly and even exhibited an increase in percentage compared with WT NK cells (Fig. 6 A) . Activation and maturation of virus-specific Ifnar −/− NK cells were nearly identical to WT NK cells, as indicated by CD27, CD11b, and KLRG1 expression at day 7 PI (Fig. 6, B-D) . Furthermore, Ifnar −/− NK cells of a comparable phenotype to WT NK cells could be recovered at >4 wk PI (Fig. 6, E-G) , revealing the ability of Ifnar −/− NK cells to generate a long-lived memory pool during infection in hosts lacking WT NK cells. Bar graph shows percentages of divided and nondivided NK cells at day 4 PI for each group. (B) FLI CA incorporation is shown in plots, and bar graph shows percentages of FLI CA + NK cells in each group. Data are mean ± SEM and representative of three independent experiments with at least n = 3 biological replicates per condition. *, P < 0.05 using paired Student's t test.