ABSTRACT 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. IMPORTANCE Gammaherpesviruses 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.
Johansen et al. (Fri,) studied this question.