Epigenetic regulation of pathogen-specific effector and memory CD4 T cells

摘要 病原体特异性的、功能不同的CD 4辅助性T细胞亚群，包括T滤泡辅助细胞（Tfh）和T淋巴细胞（T淋巴细胞）。 辅助1型（Th 1）亚群对于协调先天性和适应性免疫系统的诱导和成熟至关重要。 免疫反应。调节免疫需要Tfh和Th 1分化的适当遗传编程 清除原发性感染的反应，并促进长期记忆CD 4 T细胞介导的保护， 病原体再暴露。研究CD 4 T细胞分化的遗传学方法主要集中在 转录编程，但基因调控也与表观遗传修饰密切相关， 代表了我们对CD 4 T细胞生物学理解的一个主要知识缺口。在这个项目中，申请人将 研究10 - 11-易位（泰特）家族成员在效应子形成和功能中的作用。 以及记忆性Th 1和Tfh细胞亚群。新的初步数据显示，CD 4 T细胞的发育倾斜 在缺乏特定泰特家族成员的情况下，这个项目的目标是使用条件 遗传和嵌合方法，加上强大的传染病免疫学系统，以建立 对表观遗传编程的作用和功能的全新和机械的理解， 控制Tfh和Th 1 CD 4细胞的命运。第一组目标是评估CD 4 T细胞缺乏的功能。 特定的泰特家族成员。第二组目标是研究分子遗传机制 控制CD 4 T细胞分化。在成功完成拟议的研究后，申请人将 已经获得了涉及高维数据集的生成和分析的技能， 智力和科学丰富的密集和跨学科的指导环境。而且这个 研究金申请提供了重要的机会，发展技能，进行实验研究 并将结果传达给广泛的科学受众，这将使申请人成为成功的科学家。 独立调查员，以应对新出现的传染病带来的挑战。

ABSTRACT Pathogen-specific, functionally distinct subsets of CD4 helper T cells, including T follicular helper (Tfh) and T helper type 1 (Th1) subsets, are critical for orchestrating the induction and maturation of innate and adaptive immune responses. Proper genetic programming of Tfh and Th1 differentiation is required for regulating immune responses to clear primary infections and promote long-lived memory CD4 T cell-mediated protection against pathogen re-exposures. Genetic approaches to study CD4 T cell differentiation have been largely focused on transcriptional programming, but gene regulation is also critically tied to epigenetic modifications, which represents a major knowledge gap in our understanding of CD4 T cell biology. In this project, the applicant will investigate the role of Ten-eleven-translocation (TET) family members in the formation and function of effector and memory Th1 and Tfh cell subsets. New preliminary data show substantial CD4 T cell developmental skewing towards Tfh fates in the absence of specific TET family members. The goals of this project are to use conditional genetic and chimeric approaches, coupled with robust systems of infectious disease immunology, to establish fundamentally new and mechanistic understanding of the role and function of epigenetic programming in governing Tfh and Th1 CD4 cell fate. The first set of objectives are to evaluate the function CD4 T cells lacking specific TET family members. The second set of objectives are to study the molecular genetic mechanisms governing CD4 T cell differentiation. At the successful completion of the proposed research, the applicant will have acquired skillsets that involve the generation and analysis of high-dimensional data sets, undertaken in an intellectually and scientifically rich environment of intensive and interdisciplinary mentorship. Additionally, this fellowship application provides critical opportunities to develop skills in conducting experimental investigations and communicating results to a broad scientific audience, which will position the applicant to succeed as an independent investigator to address the challenges posed by emerging infectious diseases.