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Epigenetic programming of T follicular helper cell differentiation

滤泡辅助 T 细胞分化的表观遗传编程

基本信息

批准号：
10425393
负责人：
Jeffrey Scott Hale
金额：
$ 58.17万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-06 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10425393
关键词：
Acute Affinity Animals Antibodies Antibody Affinity Antibody Response Antibody-mediated protection B-Lymphocytes CD4 Positive T Lymphocytes Cell Differentiation process Cell Lineage Cell physiology Cells Cellular Immunology Communicable Diseases DNA Methylation DNA Methyltransferase Inhibitor DNA Modification Methylases DNA methyltransferase inhibition DNMT3a Data Decitabine Differentiated Gene Dioxygenases Effector Cell Enzymes Epigenetic Process Equilibrium Evaluation Family Gene Expression Gene Silencing Generations Genes Genetic Transcription Goals Helper-Inducer T-Lymphocyte Immune Immune response Immunity Immunization Immunoglobulin Class Switching Immunologic Memory Immunotherapy Impairment Individual Infection Influenza Laboratories Maintenance Mediating Memory Memory B-Lymphocyte Methylation Methyltransferase Modeling Mus Oxygenases Pathway interactions Pharmacology Phenotype Plasma Cells Process Reaction Regulation Regulatory Element Reporting Role Signal Transduction Structure of germinal center of lymph node T cell differentiation T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Transcription Repressor Vaccination Viral Virus Virus Diseases demethylation experimental study improved insight novel novel strategies programs response transcription factor vaccination strategy whole genome

项目摘要

Project Summary T follicular helper cells (Tfh) are a specialized subset of T cells that directly provide help to B cells to form germinal centers. Within germinal centers, B cells undergo affinity maturation of antibodies, class switching, and differentiation of long-lived plasma cells and memory B cells. T follicular helper responses are vital to long-lived antibody-mediated immune protection, which is demonstrated by the absence of long-lived antibody responses and the presentation of immune deficiency in Tfh-deficient individuals and animals. Following activation of naïve CD4 T cells by viral infection or immunization, these newly activated T cells interpret various signals that induce transcription factors that direct specific gene expression changes. In coordination with these gene expression changes that occur during T helper cell differentiation, genes undergo DNA methylation changes at CpG motifs in regulatory elements that control expression or relevant genes. DNA methylation acts as a repressive epigenetic mark, and the process of demethylation is associated with the ability to express genes important for cell function. Changes in methylation are catalyzed by Tet dioxygenases that participate in the processes of demethylation, and DNA methyltransferases that promote new (de novo) methylation to turn off irrelevant genes. The broad objectives of the specific aims in this proposal are to gain understanding of how T follicular helper cells undergo DNA methylation programing, either through demethylation or de novo methylation, and whether manipulation of such programing can enhance or impair T follicular helper cell function and thus influence antibody responses to vaccination or infection. The specific aims for this proposal are: Aim 1) Determine the role of Tet2 in regulating the balance of T follicular helper and Th1 cell and memory cell differentiation; Aim 2) Define the role of de novo methylation in regulating Tfh and Th1 memory cell differentiation and lineage commitment; and Aim 3) Determine whether DNA methyltransferase inhibition can promote Tfh differentiation and enhance antibody-mediated immune protection following immunization against influenza challenge. These studies will utilize cellular immunology approaches, gene expression and whole genome DNA methylation analyses, and immunization and infectious disease challenge to evaluate the importance of DNA methylation programing in T follicular helper cell differentiation, function, and memory formation. Together, these aims will combine to provide a mechanistic evaluation of how T follicular helper cells differentiate and identify and characterize novel pathways that can be targeted to generate more effective vaccination strategies that can improve long-lasting immunity.

项目概要滤泡辅助 T 细胞 (Tfh) 是 T 细胞的一个特殊亚群，可直接帮助 B 细胞形成生发中心。在生发中心内，B 细胞经历抗体亲和力成熟、类别转换、以及长寿命浆细胞和记忆 B 细胞的分化。 T 滤泡辅助反应对于长效抗体介导的免疫保护，通过不存在长效抗体来证明 Tfh 缺陷的个体和动物的反应和免疫缺陷的表现。下列的通过病毒感染或免疫激活初始 CD4 T 细胞，这些新激活的 T 细胞解释了各种诱导转录因子指导特定基因表达变化的信号。协调这些基因表达变化发生在 T 辅助细胞分化过程中，基因经历 DNA 甲基化控制表达或相关基因的调控元件中 CpG 基序的变化。 DNA甲基化作用作为抑制性表观遗传标记，去甲基化过程与表达能力相关对细胞功能很重要的基因。甲基化的变化由 Tet 双加氧酶催化，参与去甲基化过程以及促进新的（从头）甲基化转变的 DNA 甲基转移酶去掉不相关的基因。本提案中具体目标的总体目标是了解如何滤泡辅助 T 细胞通过去甲基化或从头进行 DNA 甲基化编程甲基化，以及操纵此类编程是否会增强或损害滤泡辅助性 T 细胞功能，从而影响抗体对疫苗接种或感染的反应。本提案的具体目标目的 1) 确定 Tet2 在调节滤泡辅助 T 细胞和 Th1 细胞平衡及记忆中的作用细胞分化；目标 2) 明确从头甲基化在调节 Tfh 和 Th1 记忆细胞中的作用分化和血统承诺；目标 3) 确定 DNA 甲基转移酶抑制是否可以促进 Tfh 分化并增强抗体介导的免疫保护流感挑战。这些研究将利用细胞免疫学方法、基因表达和整体基因组 DNA 甲基化分析以及免疫和传染病挑战，以评估 DNA 甲基化编程在滤泡辅助 T 细胞分化、功能和记忆中的重要性形成。这些目标将结合起来，对滤泡辅助 T 细胞如何发挥作用提供机械评估。细胞分化、识别和表征新的途径，可以有针对性地产生更有效的可以提高持久免疫力的疫苗接种策略。