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

摘要 病原体特异的、功能不同的CD4辅助T细胞亚群，包括T滤泡辅助T细胞(TFH)和T 辅助者类型1(Th1)亚群对于协调先天和适应性的诱导和成熟至关重要 免疫反应。调节免疫需要适当的Tfh和Th1分化的遗传程序 清除原发感染和促进长寿记忆CD4T细胞介导的免疫保护的反应 病原体再次暴露。研究CD4T细胞分化的遗传学方法在很大程度上受到了关注 转录编程，但基因调控也与表观遗传修饰密切相关，这 代表了我们在理解CD4T细胞生物学方面的主要知识差距。在这个项目中，申请者将 Ten-11易位(Tet)家族成员在效应器形成和功能中的作用 以及存储器Th1和TFH细胞子集。新的初步数据显示CD4T细胞发育严重倾斜 在没有特定的TET家庭成员的情况下，TFH的命运。此项目的目标是使用条件 基因和嵌合方法，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性的理解 主宰着TFH和Th1CD4细胞的命运。第一组目标是评估CD4T细胞缺乏的功能 特定的TET家庭成员。第二组目标是研究分子遗传机制。 控制CD4T细胞分化。在成功完成建议的研究后，申请人将 获得了涉及高维数据集的生成和分析的技能，在 智力和科学知识丰富的密集和跨学科指导环境。此外，这一点 奖学金申请提供了发展进行实验研究的技能的关键机会 并将结果传达给广大的科学受众，这将使申请者成为一个成功的 作为一名独立调查员，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.