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

描述（由申请人提供）：由分泌抗体的B细胞（浆细胞或pc）产生的抗体（Abs）是清除许多病毒病原体（包括甲型流感）所必需的，并提供关键的一线保护，防止再次感染。事实上，目前绝大多数抗病毒疫苗都是有效的，因为疫苗会引起中和性抗体，积极预防感染。尽管抗病毒PC在预防病毒感染方面很重要，但我们对病毒特异性B细胞在感染后是如何被诱导的，以及这些B细胞是如何被选择成长寿命的PC和记忆B细胞亚群，在再次暴露于同一病原体后提供保护的知之甚少。事实上，我们仍然不明白为什么有些疫苗提供终身保护，而另一些疫苗只在短时间内有效。因此，本提案的目标是确定启动病毒特异性长寿命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依赖ifn γ的病毒诱导的T-box转录因子信号通路，该信号通路控制B细胞生发中心的命运决定和病毒特异性长寿命pc的后续发展。本提案将解决的中心假设是，B细胞对病毒的免疫是由病毒诱导的炎症细胞因子环境调节的，该环境控制T-box转录因子的表达，如T-bet和Eomes，它们调节生发中心病毒特异性B细胞的细胞命运决定。本建议的目的是：(i)确定T-box转录因子、T-bet和Eomes之间的平衡，差异影响生发中心B细胞前体的长寿命pc和记忆B细胞的发育（ii）鉴定启动T-box转录因子细胞命运决定途径所需的关键细胞和细胞因子以及（ii）检查IFNγ/T-bet信号通路是否积极参与人类B细胞对病毒感染或抗病毒疫苗接种的反应。这项拟议的研究意义重大，因为我们将首次确定T-box转录因子如何控制B细胞命运的决定，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，这些实验将增进我们对如何产生和维持持久的病毒体液免疫的理解，并将提高我们设计针对一系列致病性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.