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

Abstract

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.

Transcription Factor Runx3 Regulates Interleukin-15-Dependent Natural Killer Cell Activation

“…It was previously reported that the TFs Blimp1 and Ets1 negatively regulate NKC proliferation in response to IL-15 (53,58), while the ETS TF-family member Pu.1 positively regulates the proliferative response to IL-2 (51). More recently, members of the E2F TF family known to control the cell cycle were implicated in NKC IL-15 signaling (67). Only a few Runx3 target genes were identified using NK cell lines (37,69), and no information is available about the Runx3-mediated transcriptional program regulating the NKC response to IL-15.…”

“…Conditional KO mice lacking expression of Runx3 only in NKC could certainly support the conclusion of Runx3 cell-autonomous function in NKC. However, our attempts to use Runx3 (67). In this regard, it is of interest to note that Runx3 was recently identified as one of the sustained effector genes induced in murine cytomegalovirus (MCMV)-infected Ly49H ϩ NKC during clonal expansion (61).…”

Hcmv-miR-UL112 attenuates NK cell activity by inhibition type I interferon secretion

“…Previous studies on mouse CMV (MCMV) infection have shown that cytokines like type I IFNs are secreted upon virus challenge, and this response regulates the NK-cell response [29]. Thus, we tested whether type I IFNs were involved in hcmv-miR-UL112-induced NK cell cytotoxicity regulation.…”

NK cells and interferons

“…Many studies have shown that type I IFNs can directly activate NK cells [32][33][34]; however counterevidence argues that a direct action of type I IFNs is not necessarily required to efficiently activate NK cells [35][36][37].…”