The Identification of Novel Mechanisms to Regulate B cell Responses During Adaptive Immunity

Initiation of the germinal center reaction during T-dependent adaptive immune responses gives rise to long-lived plasma cells (PCs) that produce high affinity, class switched antibodies. It also produces memory B cells to ensure a rapid, high affinity response to future pathogen exposure. Long-lived antibody and memory B cell responses underlie the success of vaccines and provide the host with durable, long-lasting protection from infectious disease. Although, the formation and maintenance of memory B cells and plasma cells are of critical importance, the mechanisms regulating these processes are poorly understood. Our lab has been interested in understanding the role of dendritic cells in regulating the germinal center reaction and adaptive immune response. We found that the formation of antigen/antibody immune complexes stimulate dendritic cells, through CD16 (FcgRIII), to secrete BAFF, a cytokine required initiation and maintenance of the germinal center as well as the formation of memory B cells. Specifically, our results indicate that DC-derived BAFF initially impacts the formation of T follicular helper cells, which are critical in seeding and initiating the germinal center response. Studies show that upon immunization with a T-dependent antigen, mice that lack CD16 expression, as well as mice lacking BAFF production by hematopoeitic cells, display reduced numbers of T follicular helper cells, and as consequence, reduced germinal center number and size. Correlated with this deficit in germinal centers, these mice also display attenuated secondary immune responses, and fewer numbers of antigen-experienced memory B cells. This suggests that DCs and BAFF play a key role in germinal center dynamics and subsequent memory B cell formation and function. Collectively, our data highlight an additional role for BAFF in the initiation and maintenance of T-dependent adaptive immune responses.Doctor of Philosoph