The transcription factor IRF8 regulates natural killer cell development and response to cytomegalovirus infection

Interferon regulatory factor 8 (IRF8) is a transcription factor critical for specifying monocyte and dendritic cell lineage fate and for directing B cell development, yet its function in natural killer (NK) cells is not understood. NK cells are innate lymphocytes that develop in the bone marrow and are capable of antigen-specific clonal proliferation. We observe in mixed bone marrow chimeric mice that despite a prevalent NK progenitor (NKP) population compared to wild-type, peripheral Irf8 −/− NK cells exhibit proper maturation and full functionality. However, using an adoptive transfer system, we demonstrate that IRF8 is indispensable for robust expansion of NK cells in response to mouse cytomegalovirus (MCMV). Consistent with this finding, Ly49H + NK cells upregulate Irf8 transcript during the early stages of MCMV infection. Furthermore, the Irf8 locus is dynamically regulated upon activation, showing extensive STAT4 binding at promoter and enhancer regions, and upregulation of the activating epigenetic marks H3K4me3 and H3K4Ac27. Thus, our work elucidates the functional contribution of IRF8 during NK cell development and antiviral responses.