Differential Responses of Immune Cells to Type I Interferon Contribute to Host Resistance to Viral Infection

Type I interferons (IFNs) are central to antiviral defense, but how they orchestrate immune cell function is incompletely understood. We determined that IFNs produced during murine cytomegalovirus (MCMV) infection differentially affect dendritic cells (DCs) and natural killer (NK) cells. IFNs induce cell-intrinsic responses in DCs, activating antiproliferative, antiviral, and lymphocyte-activating gene networks, consistent with high activity of the transcription factor STAT1 in these cells. By comparison, NK cells exhibit lower STAT1 expression and reduced IFN responsiveness. Rather, IFNs indirectly affect NK cells by inducing IL-15, which activates the transcription factor E2F and stimulates genes promoting cell expansion. IFN cell-intrinsic responses are necessary in DCs, but not NK cells, for MCMV resistance. Thus, sensitivity to IFN-induced cytokines and differences in IFN receptor signaling program immune cells to mount distinct responses that promote viral control. [Display omitted] ► Type I IFNs mediate different effects on DCs and NK cells during MCMV infection ► Type I IFNs shape antiviral DC responses in a cell-intrinsic, ISGF3-dependent manner ► NK cell activity is indirectly affected by type I IFNs via IL-15 → PI3K → E2F signals ► MCMV control requires type I IFN cell-intrinsic responses in DCs, but not NK cells