Regulation of memory T cell differentiation and long-term maintenance

项目概要/摘要 项目 3（戈德拉斯） 为了应对感染，许多细胞因子协同指导 T 细胞通过其扩增和 分化为介导病原体清除的效应细胞和持续提供长期作用的记忆细胞 保护活宿主免受再次感染。利用记忆 T 细胞的功能和寿命是基础 对于某些疫苗来说，它已成为癌症免疫治疗中一种有吸引力的方法。然而，内存T 细胞库是异质的，目前尚不清楚哪些亚群在恶性肿瘤期间提供最佳保护 或感染以及这些子集是如何转录编程的。我们建议定义转录 和感染后记忆 T 细胞亚群分化的染色质调节因子，并确定那些 促进抗肿瘤细胞毒性淋巴细胞的积累和功能。进一步，我们将探讨这种关系 染色质构型的变化和记忆 T 细胞特异性转录程序之间的变化。我们建议 高度协作的目标，利用 Crotty 独有的专业知识、基础设施和技术 Pipkin-Goldrath 实验室和核心。具体来说，我们将：（1）解决功能异质性和 循环 CD8 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、效应器和组织驻留 CD8 T 细胞亚群的表观遗传编程。 (3) 解析 Blimp1 和 Bcl6 在编程不同 CD4 记忆 T 细胞群中的作用。 (4) 剖析 染色质调节因子 CTCF 指导记忆 T 细胞分化的机制。由 了解控制记忆 T 细胞亚群分化和功能的因素 可能在感染、恶性肿瘤和免疫病理学背景下诱导或调节它们的活性。

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.