Type I Interferon receptor on NK cells negatively regulates interferon-γ production
FRONTIERS IN IMMUNOLOGY(2019)
Abstract
NK cells are a key antiviral component of the innate immune response to HSV-2, particularly through their production of IFN-gamma. It is still commonly thought that type I IFN activates NK cell function; however, rather than requiring the type I IFN receptor themselves, we have previously found that type I IFN activates NK cells through an indirect mechanism involving inflammatory monocytes and IL-18. Here, we further show that direct action of type I IFN on NK cells, rather than inducing IFN-gamma, negatively regulates its production during HSV-2 infection and cytokine stimulation. During infection, IFN-gamma is rapidly induced from NK cells at day 2 post-infection and then immediately downregulated at day 3 post-infection. We found that this downregulation of IFN-gamma release was not due to a loss of NK cells at day 3 post-infection, but negatively regulated through IFN signaling on NK cells. Absence of IFNAR on NK cells led to a significantly increased level of IFN-gamma compared to WT NK cells after HSV-2 infection in vitro. Further, priming of NK cells with type I IFN was able to suppress cytokine-induced IFN-gamma production from both human and mouse NK cells. We found that this immunosuppression was not mediated by IL-10. Rather, we found that type I IFN induced a significant increase in Axl expression on human NK cells. Overall, our data suggests that type I IFN negatively regulates NK cell IFN-gamma production through a direct mechanism in vitro and during HSV-2 infection.
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Key words
NK cells,type I IFN,IFN-gamma,HSV,Human NK cells
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