Regulation of memory T cell differentiation and long-term maintenance

记忆T细胞分化和长期维持的调节

• 批准号: 10024589
• 负责人: Ananda W Goldrath
• 金额: $ 50.91万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10024589
• 关键词: CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Characteristics; Chromatin; Chromatin Modeling; Consequentialism; Data; Dependence; Effector Cell; Epigenetic Process; Exposure to; Generations; Genetic Transcription; Genome; Goals; Heterogeneity; Human; Immunity; In Situ; Infection; Infrastructure; Laboratories; Longevity; Lymphocyte; Lymphoid; Maintenance; Malignant Neoplasms; Mediating; Memory; Population; Regulation; Role; Site; Source; T cell differentiation; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Tissues; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Vaccines; Virus Diseases; base; cancer immunotherapy; clinically relevant; cytotoxic; effector T cell; experimental study; flexibility; immunopathology; in vivo; memory CD4 T lymphocyte; novel; pathogen; programs; response; small hairpin RNA; stem; transcription factor; tumor; tumor microenvironment

PROJECT SUMMARY / ABSTRACT Project 3 (Goldrath) In response to infection, many cellular factors cooperate to direct T cells through their expansion and differentiation to effector cells that mediate pathogen clearance and memory cells that persist to provide long- lived host protection from reinfection. Harnessing the functionality and longevity of memory T cells is the basis for some vaccines and has become an attractive approach in cancer immunotherapy. However, the memory T cell pool is heterogeneous, and it is currently unclear which subsets confer optimal protection during malignancy or infection and how these subsets are transcriptionally programmed. We propose to define the transcriptional and chromatin regulatory factors of memory T cell subset differentiation following infection and identify those that promote accumulation and function of anti-tumor cytotoxic lymphocytes. Further, we will explore the relationship between changes in chromatin configuration and memory T cell-specific transcriptional programs. We propose highly collaborative Aims which leverage the expertise, infrastructure and technologies unique to the Crotty- Pipkin-Goldrath laboratories and Cores. Specifically, we will: (1) Resolve the functional heterogeneity and transcriptional programming of circulating CD8 memory T cell populations. (2) Define the transcriptional and epigenetic programming of stem-like memory, effector, and tissue-resident CD8 T cell subsets in tumors. (3) Resolve the roles of Blimp1 and Bcl6 in programming distinct CD4 memory T cell populations. (4) Dissect the mechanism(s) by which the chromatin regulatory factor CTCF instructs memory T cell differentiation. By developing an understanding of the factors that control differentiation and function of memory T cell subsets, it may be possible to induce or regulate their activity in the context of infection, malignancy, and immunopathology.

项目总结/摘要 项目3（Goldrath） 在对感染的应答中，许多细胞因子协同引导T细胞通过它们的扩增， 分化为介导病原体清除的效应细胞和持续提供长期免疫的记忆细胞。 保护宿主免受再感染。利用记忆T细胞的功能和寿命是基础 并且已经成为癌症免疫治疗中有吸引力的方法。然而，记忆T 细胞库是异质性的，目前还不清楚哪些亚群在恶性肿瘤期间提供最佳保护 以及这些亚群是如何转录编程的。我们建议定义转录 以及感染后记忆T细胞亚群分化的染色质调节因子，并鉴定那些 促进抗肿瘤细胞毒性淋巴细胞的积累和功能。此外，我们还将探讨 染色质构型的变化和记忆T细胞特异性转录程序之间的关系。我们提出 高度协作的目标，利用Crotty特有的专业知识、基础设施和技术， Pipkin-Goldrath实验室和核心。具体而言，我们将：（1）解决功能异质性， 循环CD 8记忆T细胞群的转录编程。(2)定义转录和 肿瘤中干细胞样记忆、效应子和组织驻留CD 8 T细胞亚群的表观遗传编程。（三） 解决Blimp 1和Bcl 6在编程不同的CD 4记忆T细胞群中的作用。(4)解剖 染色质调节因子CTCF指导记忆T细胞分化的机制。通过 发展对控制记忆T细胞亚群的分化和功能的因素的理解， 可能在感染、恶性肿瘤和免疫病理学的背景下诱导或调节其活性。