Priming of Natural Killer Cells by Nonmucosal Mononuclear Phagocytes Requires Instructive Signals from Commensal Microbiota

Mononuclear phagocytes are an important component of an innate immune system perceived as a system ready to react upon encounter of pathogens. Here, we show that in response to microbial stimulation, mononuclear phagocytes residing in nonmucosal lymphoid organs of germ-free mice failed to induce expression of a set of inflammatory response genes, including those encoding the various type I interferons (IFN-I). Consequently, NK cell priming and antiviral immunity were severely compromised. Whereas pattern recognition receptor signaling and nuclear translocation of the transcription factors NF-κB and IRF3 were normal in mononuclear phagocytes of germ-free mice, binding to their respective cytokine promoters was impaired, which correlated with the absence of activating histone marks. Our data reveal a previously unrecognized role for postnatally colonizing microbiota in the introduction of chromatin level changes in the mononuclear phagocyte system, thereby poising expression of central inflammatory genes to initiate a powerful systemic immune response during viral infection. [Display omitted] ► Nonmucosal NK cells from germ-free mice have impaired function ► Mononuclear phagocytes of germ-free mice fail to produce IFN-I ► Germ-free mice are susceptible to systemic viral infections ► Microbiota poises IFN-I gene expression at the level of chromatin