Ezh2 regulates follicular helper T cell differentiation

T细胞依赖性抗体应答构成了针对病原体的必要保护。滤泡辅助 T（TFH）细胞为B细胞提供关键帮助，以通过生殖中心有效产生高亲和力抗体 (GC)B细胞、长寿命浆细胞和记忆B细胞的产生。TFH-B细胞的协同性是 疫苗诱导的免疫记忆和自身免疫性疾病的发病机制。了解如何 TFH细胞的发育和功能是配制新的、更有效的疫苗的先决条件。 Ezh2具有组蛋白甲基转移酶（HMT）活性，是Polycomb中唯一的酶组分 抑制性复合物2，其部署H3K27me3抑制性组蛋白标记用于基因抑制。EZ2批评 调节T辅助细胞1、2和调节性T细胞的细胞因子产生和谱系稳定性，但尚未被证实。 TFH细胞的研究。使用体内病毒感染模型，我们的初步研究表明Ezh2是 在TFH细胞中进行性诱导和Ezh2的遗传消除损害TFH分化。ezh2表达 在SLE小鼠模型中的致病性TFH细胞中也升高。我们假设Ezh2使用 促进TFH分化和记忆TFH形成的多方面机制。我们的具体目标是： 具体目标1。阐明Ezh2促进TFH分化的遗传程序。 具体目标2。剖析Ezh2在TFH细胞表观基因组和TFH基因调控中的需求 可访问性。 总的来说，这些体内感染和蛋白质免疫模型将使我们能够定义功能性免疫缺陷。 在效应期和记忆期，TFH分化需要Ezh2。系统遗传解剖 将确定"什么" Ezh2靶基因是在TFH计划，并进一步描绘"如何" Ezh2调节其功能。 下游靶点，从而为保护性效应子和记忆TFH的产生提供机制见解 细胞因为过度旺盛的TFH细胞活性和过量的抗体产生是 几种自身免疫性疾病拟议的研究可能会产生重要的知识， 增强疫苗效力和鉴定作为治疗自身免疫性疾病的治疗靶点的新途径 条件

T cell-dependent antibody responses constitute essential protection against pathogens. Follicular helper T (TFH) cells provide critical help to B cells for effective production of high-affinity antibodies by germinal center (GC) B cells, generation of long-lived plasma cells and memory B cells. The TFH-B cell cooperativity underlies immunological memory induced by vaccines and pathogenesis of autoimmune disorders. Understanding how TFH cells develop and function is a prerequisite for formulating new, more efficacious vaccines. Ezh2 has histone methyltransferase (HMT) activity and is the sole enzymatic component in Polycomb repressive complex 2 that deploys the H3K27me3 repressive histone mark for gene repression. Ezh2 critically regulates cytokine production and lineage stability of T helper 1, 2, and regulatory T cells but has not been studies in TFH cells. Using an in vivo viral infection model, our preliminary studies showed that Ezh2 was progressively induced in TFH cells and genetic ablation of Ezh2 impaired TFH differentiation. Ezh2 expression was also elevated in pathogenic TFH cells in an SLE mouse model. We hypothesize that Ezh2 uses multipronged mechanisms to promote TFH differentiation and memory TFH formation. Our specific aims are: Specific Aim 1. To elucidate the genetic program controlled by Ezh2 in promoting TFH differentiation. Specific Aim 2. To dissect the requirements for Ezh2 in regulation of TFH cell epigenome and TFH gene accessibility. Collectively, these in vivo infection and protein immunization models will allow us to define the functional requirements for Ezh2 in TFH differentiation at both effector and memory phases. Systematic genetic dissection will determine “what” Ezh2 target genes are in the TFH program and further delineate “how” Ezh2 regulates its downstream targets, thus providing mechanistic insights into generation of protective effector and memory TFH cells. Because over-exuberant TFH cell activity and excessive antibody production underlie pathogenesis of several autoimmune disorders. The proposed studies will likely yield important knowledge necessary for enhancing vaccine efficacy and for identifying new pathway(s) as therapeutic targets for treating autoimmune conditions.