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 whether host NK cells were killing Ifnar −/− NK cells, we transferred equal numbers of WT and Ifnar −/− NK cells into WT or perforin-deficient (Prf1 −/− ) hosts and infected them with lymphocytic choriomeningitis virus (LCMV). LCMV infection elicits a strong type I IFN response (Biron et al., 1999) but does not drive the antigen-specific proliferation of Ly49H + NK cells observed during MCMV infection, thus ruling out the influence of the m157-Ly49H interaction in determining relative NK cell numbers. After adoptive transfer and LCMV infection in WT hosts, WT NK cells persisted, whereas the percentage of Ifnar −/− NK cells diminished at day 7 PI (Fig. 5 A) . The decrease in Ifnar −/− NK cells was seen as early as day 3 PI (not depicted). However, Ifnar −/− NK cells transferred into Prf1 −/− hosts were able to persist, and larger percentages were observed compared with the cotransferred WT NK cell population (Fig. 5 A) , uncovering a novel role for type I IFNs in protecting NK cells against perforin-mediated elimination. Similar results were observed when we infected mice with an MCMV strain lacking m157 (not depicted). To confirm that the elimination of Ifnar −/− NK cells in WT mice was caused by host NK cells and not CD8 + T cells or another cell source, we transferred equal numbers of WT and Ifnar −/− NK cells into WT or NKp46 Cre × R26 DTA hosts and infected them with LCMV. NKp46 Cre × R26 DTA mice express the Cre recombinase under the control of the NKp46 promoter and possess a loxP-flanked stop cassette followed by a diphtheria toxin A, thus creating a host where all NK cells are ablated. LCMV infection revealed a predominance of transferred WT NK cells compared with Ifnar −/− NK cells in WT hosts, which was not observed in NKp46 Cre × R26 DTA hosts (Fig. 5 A) . Similar to the perforin-deficient hosts, NKp46 Cre × R26 DTA hosts revealed a higher percentage of Ifnar −/− NK cells compared with WT NK cells after infection. Thus, these findings support a perforin-dependent NK cell-mediated elimination of NK cells that are unable to sense type I IFNs during viral infection.