Cutting Edge: STAT1-Mediated Epigenetic Control of Rsad2 Promotes Clonal Expansion of Antiviral NK Cells

NK cells represent a cellular component of innate immunity but possess features of adaptive immunity, including clonal expansion and establishment of long-lived memory following infection. During mouse CMV (MCMV) infection, we observed (which encodes Viperin) to be among the most highly induced IFN stimulatory genes in activated NK cells, correlating with increased chromatin accessibility at the gene locus. Furthermore, in NK cells stimulated with IFN-α, the promoter region of was enriched for STAT1 binding and the permissive histone mark H3K4me3. IFN-αR- and STAT1-deficient NK cells showed an impairment of induction and chromatin accessibility during MCMV infection. Finally, Rsad2-deficient NK cells were defective in clonal expansion and memory formation following exposure to MCMV, in part because of greater apoptosis. Thus, our study reveals a critical mechanism of STAT1-mediated epigenetic control of to promote the adaptive behavior of NK cells during viral infection.