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

病原体特异性效应细胞和记忆 CD4 T 细胞的表观遗传调控

基本信息

批准号：
10311459
负责人：
Jordan T Johnson
金额：
$ 3.26万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311459
关键词：
Activities of Daily Living Acute Address Adopted B-Cell Lymphoma 6 Protein B-Lymphocytes BLR1 gene Biological Assay Biology Bone Marrow CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Differentiation process Cell physiology Cells Cellular biology Chimera organism Chromatin Communicable Diseases Coupled DNA Data Data Set Development Emerging Communicable Diseases Environment Enzymes Epigenetic Process Exhibits Family member Fellowship Gene Expression Gene Expression Regulation Generations Genetic Genetic Programming Genetic Transcription Goals Helper-Inducer T-Lymphocyte Immune Immune response Immunity Impairment Individual Infectious Disease Immunology Interferon Type II Interleukin-10 Interleukin-2 Interleukin-4 Investigation Kinetics Knockout Mice Knowledge Link Measures Mediating Memory Mentorship Messenger RNA Methylation Modification Molecular Genetics Natural Immunity Peripheral Phagocytes Play Positioning Attribute Primary Infection Production Protein Family Reaction Regulation Research Research Personnel Resistance to infection Resolution Role SLAM protein Structure of germinal center of lymph node System T cell differentiation T cell regulation T cell response T-Lymphocyte Subsets TNF gene Testing Th1 Cells Transgenic Organisms Vaccination Virus Virus Diseases acute infection adaptive immune response adaptive immunity antiviral immunity base chronic infection conditional knockout cytokine demethylation epigenetic regulation experimental study genetic approach in vivo memory CD4 T lymphocyte multidimensional data oxidation pathogen programmed cell death protein 1 programs response skills thymocyte transcription factor

项目摘要

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.

抽象的病原体特异性的，功能不同的CD4辅助T细胞的子集，包括T卵泡辅助器（TFH）和T 辅助1（TH1）子集，对于安排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分化的遗传编程对清除原发性感染的反应并促进长寿记忆CD4 T细胞介导的保护病原体重新曝光。研究CD4 T细胞分化的遗传学方法已主要集中在转录编程，但基因调节也与表观遗传修饰有关，这也是如此在我们对CD4 T细胞生物学的理解中代表了一个主要的知识差距。在这个项目中，申请人将调查十个时期转换（TET）家族成员在效应子的形成和功能中的作用和内存TH1和TFH细胞子集。新的初步数据显示了大量的CD4 T细胞发育偏斜在没有特定TET家族成员的情况下，命运命运。该项目的目标是使用条件遗传和嵌合方法，再加上强大的感染性疾病免疫学系统，以建立从根本上开始对表观遗传编程的作用和功能的新机械理解治理TFH和TH1 CD4细胞命运。第一组目标是评估缺少缺乏的函数CD4 T单元特定的TET家庭成员。第二组目标是研究分子遗传机制管理CD4 T细胞分化。在成功完成拟议的研究时，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集智力和科学丰富的密集和跨学科指导的环境。另外，这个奖学金应用程序为发展实验研究的技能提供了关键的机会并将结果传达给广泛的科学受众，这将使申请人成功地成为独立研究者解决了新兴的传染病所带来的挑战。