The Role of Tbet+ B cells in viral reinfection

Abstract B cells differentiate to produce antibodies that neutralize and inhibit viral entry aiding in host protection from infections. Following infection, B cells undergo CD4 T cell-dependent maturation and differentiation either in germinal center (GCs) or extrafollicular (EF) pathways within secondary lymphoid organs. B cells that have the potential to differentiate into antibody-secreting cells (ASCs) following secondary infections such as conventional memory B cells and CD11c+Tbet+ B cells are generated via both EF and GC reactions. Yet, the specific contribution of each of these B cell subsets to the generation and activity of anti-viral antibodies upon re-infection remains unclear. CD11c+Tbet+ B cells (herein referred to as Tbet+ B cells) are a distinct B cell subset that differentiate following viral infections as well as autoimmunity in mice and humans. Emerging studies have shown that in murine and human infections, Tbet+ B cells are critical drivers of protective antibodies. Tbet+ B cells are capable of differentiating into class-switched autoantibody-secreting cells upon stimulation by cytokines and TLR agonists. Additionally, these B cells have elevated expression of MHCII and secrete inflammatory cytokines such as IFNg and IL-12 following stimulation, suggesting a role in effector T cell activation. The development of Tbet+ B cells in a primary infection has been well elucidated, but their differentiation and contribution to host protection following secondary viral infection is poorly understood. Our new data and published studies demonstrate that Tbet+ B cells develop from the GC response, but mainly arise from the EF pathway following a primary viral infection. However, whether Tbet+ B cells that arise from GC or EF origin have different functions upon re-infection is unknown. Currently, we found that following the resolution of a viral infection both the GC and EF-derived Tbet+ B cells persist in the spleen. However, upon re- infection, the GC population appears to form secondary GCs or differentiate into ASCs, while the EF maintains a Tbet+ B cell phenotype indicating a role for T cell-mediated immunity. We hypothesize that the developmental origin of Tbet+ B cells influence their differentiation and function following secondary viral infection. Accordingly, our study will dissect how GC and EF origin impact transcriptional regulation and localization of Tbet+ B cells. We will utilize an allotypic transfer system to discern the protective contributions of Tbet+ B cells versus memory B cells following re-infection. We expect this work to reveal a novel mechanism of Tbet+ B cell regulation that critically impacts the host response following infection. Ultimately, this work should provide insight into new therapeutic targets to boost antibody responses and/or effector CD4 T cell responses in immunization strategies or during secondary infection or dampen harmful humoral responses during autoimmunity.