Control of anti-viral B cell responses by IFNg, T-bet and Eomes

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Antibodies (Abs) produced by Ab-secreting B cells (plasma cells or PCs) are required for the clearance of many viral pathogens, including influenza A, and provide crucial first line protection against reinfection. Indeed, the vast majoriy of the current anti-viral vaccines are effective because the vaccines elicit neutralizing Abs that actively prevents infection. Despite the importance of anti-viral PCs in protection against virus infections, we know little about how virus-specific B cells are induced following infection or how these B cells are selected into the long-lived PC and memory B cell subsets that provide protection following re-exposure to the same pathogen. In fact, we still do not understand why some vaccines confer life-long protection while others are only effective for a short time. Therefore, the goal of this proposal is to identify the key molecular and cellular signals that initiate the development of virus-specific long-lived PCs and memory B cells. We recently identified a novel IFNγ-dependent, virus-induced T-box transcription factor signaling pathway in B cells that controls B cell fate decisions in the germinal center and the subsequent development of virus-specific long-lived PCs. The central hypothesis that will be addressed in this proposal is that B cell immunity to viruses is regulated by the virus-induced inflammatory cytokine milieu, which controls expression of T-box transcription factors, like T-bet and Eomes that regulate cell fate decisions for virus-specific B cells in the germinal center. The objectivesof this proposal are to: (i) determine whether the balance between the T-box transcription factors, T-bet and Eomes, differentially affects the development of long-lived PCs and memory B cells from the germinal center B cell precursor (ii) identify the key cells and cytokines that are required to initiate the T-box transcription factor cell fate determining pathways in B cells and (ii) examine whether the IFNγ/T-bet signaling pathway is actively engaged in human B cells responding to viral infection or anti-viral vaccination. The proposed research is significant because we will define, for the first time, how T-box transcription factors control B cell fate decisions and will learn whether vaccines that engage this cell fate pathway in B cells induce more potent and long-lasting anti-viral immunity in mouse models and human subjects. Together, these experiments will increase our understanding of how lasting humoral immunity to viruses is generated and maintained and will improve our ability to design more effective vaccines against a range of pathogenic viruses.