Mechanistic study of TGF-beta-dependent control of gut-resident memory T cells

项目摘要 传染病构成了重大的公共卫生负担，占全球死亡人数的近五分之一。 每年。大多数感染是从受限的粘膜组织开始的，如肠道。去战斗 肠道感染时，肠道常驻免疫细胞优于循环免疫细胞。最近出现了一股激增的 对组织驻留记忆T(TRM)细胞的兴趣已被证明是一种关键的适应性免疫 粘膜免疫成分。这些细胞已被标记为要生成的理想细胞群 T细胞疫苗。然而，参与肠道TRM细胞分化和维持的因素 仍然没有明确的定义。 与外周的其他T细胞群不同，肠道TRM细胞具有独特的转录网络。我们 建议同时抑制转录因子eome和诱导转录因子 RUNX3是急性感染后肠道TRM细胞正常分化和维持所必需的。 根据我们以前的发现，我们假设转化生长因子-介导了trm细胞的分化和维持。 在肠道中，通过控制依赖Eome和Runx3的转录程序。Eome和Runx3是 肠TRM细胞中转化生长因子-信号下游相对独立的结节。使用不同的遗传模型 (特异性删除T细胞上转化生长因子-受体的条件性和诱导性基因敲除小鼠，以及转化生长因子- 受体/Eome双条件基因敲除小鼠T细胞)，将解决三个主要问题： 1)肠道TRM前体细胞或肠道TRM细胞何时接收转化生长因子-信号？持续的转化生长因子- 肠道TRM细胞的维持需要信号传递吗？转录程序维护的内容是什么 通过转化生长因子-信号在肠道TRM细胞？ 2)转化生长因子依赖的转录因子eome下调在血管内皮细胞中的作用是什么 肠道TRM细胞的分化和维持？什么是转化生长因子-依赖的转录程序 这是由肠道TRM细胞中的eome阻止的吗？ 3)转化生长因子依赖于转录因子Runx3的诱导有哪些功能？不管埃默斯 和Runx3共同控制肠道TRM细胞中大部分依赖转化生长因子-的转录程序？ 这些研究的结果将阐明转化生长因子-控制的转录程序 肠道TRM细胞的分化和维持。这些研究将大大加深我们对 建立肠道TRM细胞生物学，为今后的翻译工作奠定基础。

Project Summary Infectious diseases pose a significant public health burden, accounting for nearly one-fifth of deaths globally per annum. Most infections are initiated from a restricted mucosal tissue, such as the intestine. To fight intestinal infections, gut-resident immune cells are superior to circulating ones. There is a surge of recent interest in tissue-resident memory T (TRM) cells that have been shown to be a critical adaptive immune component of mucosal immunity. These cells have been flagged as an ideal cell population to be generated in T cell-based vaccines. However, the factors involved in the differentiation and maintenance of gut TRM cells remain poorly defined. Distinct from other T cell populations in the periphery, gut TRM cells harbor a unique transcription network. We propose that simultaneously suppressing the transcription factor Eomes and inducing the transcription factor Runx3 are required for the proper differentiation and maintenance of gut TRM cells following acute infections. Based on our previous findings, we hypothesize that TGF- mediates TRM cell differentiation and maintenance in the gut through controlling Eomes- and Runx3-dependent transcription programs. Eomes and Runx3 are relatively independent nodules downstream of TGF- signaling in gut TRM cells. Using different genetic models (conditional and inducible knockout mice that specifically delete TGF- receptor on T cells, and TGF- receptor/Eomes double conditional knockout mice in T cells), three major questions will be addressed: 1) When do gut TRM precursor or gut TRM cells receive TGF- signaling? Whether continuous TGF- signaling is required for the maintenance of gut TRM cells? What is the transcription program maintained by TGF- signaling in gut TRM cells? 2) What is the function of TGF--dependent down-regulation of transcription factor Eomes in the differentiation and maintenance of gut TRM cells? What is the TGF--dependent transcription program that is prevented by Eomes in gut TRM cells? 3) What are the functions of TGF- dependent induction of transcription factor Runx3? Whether Eomes and Runx3 together control the majority of TGF--dependent transcription program in gut TRM cells? The results from these studies will elucidate the transcription program underlying TGF--controlled differentiation and maintenance of gut TRM cells. These studies will substantially further our understanding of gut TRM cell biology and lay the basis for future translational works.