Abstract
Abstract Human gammaherpesviruses, such as Epstein-Barr virus (EBV), are human specific gammaherpesviruses that establish lifelong infection in >95% of adults and are associated with multiple cancers, including B cell lymphomas. These viruses have a natural tropism for B cells and usurp B cell differentiation to drive a robust polyclonal germinal center response, needed to establish a latent reservoir in memory B cells. The viral and host factors that influence the gammaherpesvirus-driven germinal center response are not clearly defined. Murine gammaherpesvirus 68 (MHV68) is a natural rodent pathogen that is genetically and biologically related to human gammaherpesviruses and provides a tractable animal model to study viral and host factors that impact chronic infection. Utilizing MHV68, we discovered that IL-17RA signaling is proviral and supports the establishment of chronic gammaherpesvirus infection. Specifically, loss of IL-17RA signaling during MHV68 infection significantly attenuated viral latency, reactivation, and the germinal center response. Importantly, the mechanism by which IL-17A signaling promotes MHV68-driven germinal center response and latency remained unclear. To gain mechanistic insight, we generated a mouse model of T cell specific IL-17RA deficiency. Excitingly, loss of IL-17RA specifically in T cells during MHV68 infection attenuated viral latency, reactivation, and the gammaherpesvirus-driven germinal center response in the spleen, similar to what was observed in the global IL-17RA−/− model. As T cells are not infected by MHV68, our finding unveils a novel crosstalk between T cell intrinsic IL-17A signaling and gammaherpesvirus infection of B cells, including virus-driven B cell differentiation. Supported by American Cancer Society Postdoctoral Award (134165-PF-19-176-01-MPC, C.N.J.)
Published Version
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