A combination of proviral and antiviral roles of CD11c- and T-bet-expressing B cells defines parameters of chronic murine gammaherpesvirus infection

Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection and are associated with the development of cancer and multiple sclerosis. Unlike other viral families, gammaherpesviruses selectively target B cells to establish chronic infection. Specifically, gammaherpesvirus-driven differentiation of latently infected cells through the germinal center supports chronic infection and seeds viral lymphomagenesis. CD11c⁺ B cells are induced by most viral infections and are also observed in aged individuals and autoimmune diseases. Classically, CD11c⁺ B cells differentiate via an extrafollicular pathway that does not involve germinal center response, generating antibodies of beneficial (antiviral) or pathogenic (self-reactive) nature. While CD11c⁺ B cells are induced during B cell-tropic gammaherpesvirus infection, their role in chronic infection remains poorly defined. Here, we demonstrate that infection of the CD11c⁺ B cells, including those expressing germinal center markers, contributes to the overall latent gammaherpesvirus reservoir during natural infection. Both T-bet⁺ and T-bet^neg CD11c⁺ B cell subsets expanded and underwent germinal center differentiation during chronic gammaherpesvirus infection. Furthermore, B cell-intrinsic T-bet expression attenuated the long-term latent viral reservoir, gammaherpesvirus-driven germinal center responses, and differentiation of self-reactive B cells. In summary, our study for the first time defines CD11c⁺ splenic B cells as a reservoir of latent gammaherpesvirus during mucosal chronic infection and reveals an important role of T-bet⁺ B cells in controlling long-term infection and gammaherpesvirus-driven pathogenic host processes.IMPORTANCEGammaherpesviruses are ubiquitous pathogens that are associated with cancer and multiple sclerosis. These viruses selectively infect B cells and drive their differentiation through the germinal center response to establish chronic infection. Here, we demonstrate that gammaherpesvirus infection drives expansion and germinal center-based differentiation of CD11c⁺ B cells that host the latent viral reservoir. We also show that B-cell-intrinsic T-bet expression is important for control of long-term gammaherpesvirus infection and pathogenesis.