A novel proviral function for IL-17 during gammaherpesvirus infection

Abstract

Abstract Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection and are associated with B cell lymphomas. These viruses infect naïve B cells and induce a polyclonal germinal center (GC) response to establish long-term infection in memory B cells. We showed that Interferon Regulatory Factor 1 (IRF-1), an antiviral and tumor suppressor transcription factor, selectively restricts the GC reaction driven by murine gammaherpesvirus 68 (MHV68). Further, latent MHV68 infection was poorly controlled in IRF-1−/− mice, including in the peritoneal cavity where the latency is not regulated by the GC response. In our search for the mechanism underlying the observed phenotypes, we have unexpectedly found a significant increase in Th17 cells in MHV68 infected IRF-1−/− mice. Herpesvirus saimiri (HVS), a related simian gammaherpesvirus, encodes a viral IL-17, posing an intriguing possibility that IL-17 is proviral. MHV68 does not encode an IL-17 homologue, suggesting that MHV68 may rely on a host derived IL-17. Intriguingly, latent MHV68 infection was significantly attenuated in IL-17RA−/− mice establishing, for the first time, a proviral role of host IL-17 signaling during gammaherpesvirus infection. Further, there was a significant decrease in the GC B cell response in IL-17RA−/− mice following MHV68, but not LCMV infection, indicating that IL-17 signaling is selectively required to support the GC response during gammaherpesvirus infection. Altogether, our study establishes IRF-1 as a suppressor of Th17 differentiation and reveals a novel proviral role of IL-17 during gammaherpesvirus infection.