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

描述（由申请方提供）：由分泌Ab的B细胞（浆细胞或PC）产生的抗体（Ab）是清除许多病毒病原体（包括甲型流感病毒）所必需的，并提供关键的一线预防再感染保护。事实上，目前绝大多数抗病毒疫苗是有效的，因为疫苗引发积极预防感染的中和Ab。尽管抗病毒PC在保护免受病毒感染方面的重要性，但我们对病毒特异性B细胞在感染后如何诱导或这些B细胞如何被选择为长寿命PC和记忆B细胞亚群知之甚少，这些细胞亚群在再次暴露于相同病原体后提供保护。事实上，我们至今仍不明白，为何有些疫苗是终身保护，有些则只在短时间内有效。因此，本提案的目标是确定启动病毒特异性长寿PC和记忆B细胞发育的关键分子和细胞信号。我们最近在B细胞中发现了一种新的IFNγ依赖性、病毒诱导的T-box转录因子信号通路，该通路控制着B细胞在生发中心的命运决定和随后病毒特异性长寿PC的发育。本提案中将阐述的中心假设是，B细胞对病毒的免疫力受病毒诱导的炎性细胞因子环境的调节，该环境控制T盒转录因子的表达，如T-bet和Eomes，其调节生发中心中病毒特异性B细胞的细胞命运决定。本提案的目标是：（i）确定T-box转录因子、T-bet和Eomes之间的平衡，差异地影响来自生发中心B细胞前体的长寿命PC和记忆B细胞的发育，（ii）鉴定启动B细胞中的T盒转录因子细胞命运决定途径所需的关键细胞和细胞因子，和（ii）检查IFNγ/T-bet信号通路在人类B细胞对病毒感染或抗病毒疫苗接种的应答中活跃。这项拟议的研究意义重大，因为我们将首次定义T盒转录因子如何控制B细胞命运决定，并将了解在B细胞中参与这种细胞命运途径的疫苗是否在小鼠模型和人类受试者中诱导更有效和持久的抗病毒免疫。总之，这些实验将增加我们对如何产生和维持对病毒的持久体液免疫的理解，并将提高我们设计针对一系列致病病毒的更有效疫苗的能力。

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.