B cell-intrinsic interleukin 17 receptor A signaling supports the establishment of chronic murine gammaherpesvirus 68 infection.

The human-specific gammaherpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus infect >95% of all adults, establish lifelong infections, and are associated with multiple different cancers, including B-cell lymphomas. These viruses naturally infect B cells and drive a unique and robust germinal center response to establish their latent viral reservoir in memory B cells. The unique and robust nature of the virus-driven germinal center response increases the risk for B-cell transformation, which is why many gammaherpesvirus-associated cancers are derived from germinal center or post-germinal center B cells. We have previously reported that both global and T cell-specific host IL-17RA signaling is proviral in the context of gammaherpesvirus infection by promoting the virus-driven germinal center response and establishment of latent viral infection. In this study, we examine the role of B cell-specific IL-17RA signaling in the context of gammaherpesvirus infection, given these viruses' reliance on B cells to establish and maintain lifelong infection. Similarly, to what we observed in the context of global and T cell-specific IL-17RA signaling, we found that B cell-intrinsic IL-17RA signaling supports the establishment of viral latency and reactivation in the spleen and peritoneal cavity, as well as promotes the virus-driven germinal center response. Our study reveals the proviral role of B cell-intrinsic IL-17RA signaling in supporting the establishment of chronic gammaherpesvirus infection.IMPORTANCEGammaherpesviruses are lifelong pathogens that are prevalent in over 95% of all adults. These viruses are tumorigenic and associated with multiple cancers, including B-cell lymphomas. They are B-cell tropic viruses that manipulate the germinal center response to establish their latent viral reservoir in memory B cells. This manipulation of the germinal center response is thought to be the target of viral transformation, leading to lymphomagenesis as most gammaherpesvirus-associated cancers are germinal center or post-germinal center derived. In this study, we developed a new mouse model to understand the B cell-intrinsic role of IL-17RA signaling in gammaherpesvirus infection. Previous studies have shown that IL-17RA signaling is proviral in the context of gammaherpesvirus infection, and this study found that while B cell-intrinsic IL-17RA signaling is not the sole factor behind the systemic proviral role of IL-17RA signaling, it plays an important role in the virus-driven germinal center response, the expansion of B-1 B cells, and the establishment of chronic gammaherpesvirus infection.