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

Front Immunol. 2019 Jun 4;10:1261. doi: 10.3389/fimmu.2019.01261. eCollection 2019.


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.

Keywords: HSV; Human NK cells; IFN-γ; NK cells; type I IFN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Cytokines / metabolism
  • Gene Expression Regulation
  • Herpes Simplex / immunology
  • Herpes Simplex / metabolism
  • Herpes Simplex / virology
  • Herpesvirus 2, Human / physiology
  • Humans
  • Immunophenotyping
  • Interferon-gamma / biosynthesis*
  • Interleukin-10 / biosynthesis
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Lymphocyte Count
  • Mice
  • Mice, Transgenic
  • Receptor, Interferon alpha-beta / genetics
  • Receptor, Interferon alpha-beta / metabolism*


  • Biomarkers
  • Cytokines
  • Interleukin-10
  • Receptor, Interferon alpha-beta
  • Interferon-gamma