CD4+ T cell differentiation and help to B cells

Abstract

Vaccines save 2.5 million lives per year. Vaccine efficacy is largely dependent on the successful generation of antibodies by B cells for the elimination of pathogens like the influenza virus. T follicular helper (Tfh) cells are a type of CD4+ T cell that provides critical help to B cells for this process. My thesis research involves studying factors that promote Tfh cell formation and therefore B cell responses. This research is significant because it will provide better understanding of how Tfh cells are generated, which can be implemented during vaccine design. Using an approach to track both polyclonal antigen- specific CD4+ T and B cells within the same mouse after Complete Freund’s Adjuvant immunization, we found that the expression of BCOR protein in CD4+ T cells was critical for optimal Tfh formation. Reduced Tfh development as a result of BCOR absence also led to reduced germinal center B cell and antibody-secreting plasma cell formation. Thus, BCOR plays a critical role in promoting Tfh differentiation and B cell responses. The role of BCOR in CD4+ T cell differentiation was also examined after infection of mice with the extracellular pathogen Streptococcus pyogenes (Group A Streptococcus). In this context, BCOR enhanced the development of another CD4+ T cell type called T helper 17 (Th17) cells. Th17 cells promote protection by secreting cytokines, like IL-17A, that drive trafficking of neutrophils to the site of infection to kill bacteria. Identifying the drivers of Th17 cells will inform the development of a Th17- focused Streptococcus pyogenes vaccine for humans, which is currently unavailable. Because the efficacy of most vaccines is based on the process by which CD4+ T cells stimulate antibody responses, we wanted to better understand the role of different CD4+ T cell types on the B cell response. Tfh cells, in addition to Th1 and Th17 cells, were found to contribute to the production of early antibody-secreting B cells. This work provides insight into how non-Tfh cells also contribute to the B cell response, which is understudied in the field of B cell biology. Better understanding the process of CD4+ T cell help for generating antibody-secreting B cells is critical for producing efficacious vaccines.