Type I Interferon Receptor on NK Cells Negatively Regulates Interferon-γ Production

• Main Authors: Amanda J. Lee, Firoz Mian, Sophie M. Poznanski, Michele Stackaruk, Tiffany Chan, Marianne V. Chew, Ali A. Ashkar
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-06-01
• Series: Frontiers in Immunology
• Subjects: NK cells; type I IFN; IFN-γ; HSV; Human NK cells
• Online Access: https://www.frontiersin.org/article/10.3389/fimmu.2019.01261/full

NK cells are a key antiviral component of the innate immune response to HSV-2, particularly through their production of IFN-γ. 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-γ, negatively regulates its production during HSV-2 infection and cytokine stimulation. During infection, IFN-γ 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-γ 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-γ 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-γ 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-γ production through a direct mechanism in vitro and during HSV-2 infection.