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Front. Immunol. | doi: 10.3389/fimmu.2019.01261

Type I Interferon receptor on NK cells negatively regulates interferon-γ production

 Ali A. Ashkar1*,  Amanda Lee1,  Firoz Mian1, Sophie M. Poznanski1,  Michele Stackaruk1, Tiffany Chan1 and Marianne V. Chew1
  • 1McMaster University, Canada

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 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: type I IFN, HSV-2, Natural Killer cells, IFN-Y, Immune Regulation

Received: 06 Dec 2018; Accepted: 17 May 2019.

Edited by:

Marina Cella, Washington University School of Medicine in St. Louis, United States

Reviewed by:

Veronika Sexl, College of Veterinary Medicine, Philippines
Anne B. Krug, Ludwig Maximilian University of Munich, Germany  

Copyright: © 2019 Ashkar, Lee, Mian, Poznanski, Stackaruk, Chan and Chew. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Ali A. Ashkar, McMaster University, Hamilton, Canada, ashkara@mcmaster.ca