Ezh2 regulates follicular helper T cell differentiation

Ezh2 调节滤泡辅助 T 细胞分化

• 批准号: 10240753
• 负责人: Weiqun Peng
• 金额: $ 48.9万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240753
• 关键词: Ablation; Acute-Phase Reaction; Antibody Affinity; Antibody Formation; Antibody Response; Apoptosis; Autoimmune Diseases; B-Lymphocytes; Bacterial Infections; Cells; Complement; Complex; Dissection; Enhancers; Epigenetic Process; FOXP3 gene; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Transcription; Genomics; Helper-Inducer T-Lymphocyte; Histones; Immunity; Immunization; Immunologic Memory; Impairment; Infection; Intrinsic factor; Knowledge; Link; Maps; Mediating; Memory; Memory B-Lymphocyte; Methods; Modeling; Molecular; Molecular Analysis; Nuclear Localization Signal; Output; Pathogenesis; Pathogenicity; Pathway interactions; Phase; Phosphorylation; Physiological; Plasma Cells; Polycomb; Process; Production; Proteins; Regulation; Regulatory T-Lymphocyte; Repression; Role; Site; Stimulus; Structure; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T cell differentiation; T-Lymphocyte; Testing; Vaccination; Vaccines; Viral Proteins; Virus Diseases; autoimmune pathogenesis; cytokine; design; epigenome; extracellular; gene repression; histone methyltransferase; in vivo; insight; mouse model; novel; pathogen; prevent; programs; promoter; response; senescence; therapeutic target; transcription factor; transcriptomics; vaccine efficacy

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.

依赖T细胞的抗体反应构成了对病原体的基本保护。毛囊辅助对象 T(TFH)细胞为B细胞生发中心有效产生高亲和力抗体提供关键帮助 (GC)B细胞，产生长寿的浆细胞和记忆B细胞。TFH-B细胞的协同作用是基础 疫苗诱导的免疫记忆与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研制新的、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 抑制复合体2，部署用于基因抑制的H3K27me3抑制组蛋白标记。EZH2危急 调节T辅助细胞1、2和调节性T细胞的细胞因子的产生和谱系稳定性，但尚未 在TFH细胞中的研究。使用体内病毒感染模型，我们的初步研究表明Ezh2是 在TFH细胞中的进行性诱导和Ezh2的基因消融会损害TFH的分化。EZH2表达式 在SLE小鼠模型中，致病的TFH细胞中也有升高。我们假设Ezh2使用 多管齐下促进TFH分化和记忆TFH的形成。我们的具体目标是： 具体目的1.阐明Ezh2基因调控的促TFH分化的遗传程序。 具体目的2.剖析Ezh2对TFH细胞表观基因组和TFH基因调控的要求 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 Ezh2在效应和记忆阶段对TFH分化的要求。系统性遗传解剖 将确定TFH计划中的Ezh2目标基因是什么，并进一步描述Ezh2如何调节其 下游目标，从而提供对保护性效应器和记忆TFH生成的机械见解 细胞。由于过度旺盛的TFH细胞活性和过度的抗体产生是其发病机制的基础 几种自身免疫性疾病。拟议的研究可能会产生必要的重要知识 提高疫苗效力寻找自身免疫治疗靶点的新途径(S) 条件。