Cutting Edge: Cooperative interferon regulatory factor network shapes the NK-cell antiviral response

Natural killer (NK) cells are innate lymphocytes that exhibit adaptive traits particularly evident during cytomegalovirus (CMV) infection. Following mouse CMV (MCMV) infection, NK cells upregulate the transcription factors IRF4 and IRF8, which are indispensable for their survival and proliferation upon viral infection. However, it is unclear whether these factors are expressed within the same individual cell and whether deficiency in one could be compensated by the other. In this study, we observed that a subset of NK cells co-express high levels of IRF4 and IRF8 in an NFκB-dependent manner. These IRF4HighIRF8High NK cells are specifically enriched for activated but immature cells with high proliferative potential during MCMV infection. Functionally, NK cells lacking both IRF4 and IRF8 develop normally, but experience a more severe expansion defect during virus exposure compared to NK cells deficient in a single factor. Thus, our study reveals a cooperative interplay between IRF4- and IRF8-dependent transcriptional networks in regulating NK-cell antiviral responses.