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

描述（由申请人提供）：清除许多病毒病原体（包括甲型流感）需要由分泌抗体的 B 细胞（浆细胞或 PC）产生的抗体 (Ab)，并提供重要的一线保护以防止再次感染。事实上，目前绝大多数抗病毒疫苗都是有效的，因为这些疫苗能产生中和抗体，从而积极预防感染。尽管抗病毒 PC 在预防病毒感染方面非常重要，但我们对感染后如何诱导病毒特异性 B 细胞，或者这些 B 细胞如何被选入长寿命 PC 和记忆 B 细胞亚群（在再次暴露于相同病原体后提供保护）知之甚少。事实上，我们仍然不明白为什么有些疫苗可以提供终身保护，而另一些疫苗则只能短期有效。因此，该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型 IFNγ 依赖性、病毒诱导的 T-box 转录因子信号通路，该通路控制生发中心的 B 细胞命运决定以及病毒特异性长寿命 PC 的后续发育。该提案将讨论的中心假设是，B 细胞对病毒的免疫受到病毒诱导的炎症细胞因子环境的调节，该环境控制 T-box 转录因子的表达，例如 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。该提案的目标是：(i) 确定 T-box 转录因子 T-bet 和 Eomes 之间的平衡是否对来自生发中心 B 细胞前体的长寿命 PC 和记忆 B 细胞的发育产生差异性影响 (ii) 识别启动 B 细胞中 T-box 转录因子细胞命运决定通路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的反应疫苗接种。这项拟议的研究意义重大，因为我们将首次定义 T-box 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会在小鼠模型和人类受试者中诱导更有效、更持久的抗病毒免疫。总之，这些实验将增加我们对如何产生和维持针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病原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.