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。大多数感染是从限制性粘膜组织，如肠道开始的。打 肠道感染，肠道驻留免疫细胞上级循环的。最近， 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 粘膜免疫的组成部分。这些细胞被标记为理想的细胞群， T细胞疫苗然而，参与肠TRM细胞分化和维持的因素 定义不明确。 与外周中的其他T细胞群体不同，肠道TRM细胞具有独特的转录网络。我们 提出同时抑制转录因子Eomes和诱导转录因子 Runx 3是急性感染后肠道TRM细胞正确分化和维持所必需的。 基于我们以前的研究结果，我们假设TGF-β介导TRM细胞的分化和维持， 通过控制Eomes和Runx 3依赖的转录程序在肠道中。Eomes和Runx 3是 肠TRM细胞中TGF-β信号传导下游的相对独立的结节。使用不同的基因模型 （特异性缺失T细胞上的TGF-β受体的条件性和诱导性敲除小鼠，以及特异性缺失TGF-β受体的小鼠） 受体/Eomes双条件性敲除小鼠），将解决三个主要问题： 1)肠道TRM前体或肠道TRM细胞何时接受TGF-β信号传导？是否连续TGF-β 信号是维持肠道TRM细胞所必需的？什么是转录程序维护 通过肠道TRM细胞中的TGF-β信号传导？ 2)TGF-β依赖性下调转录因子Eomes在肿瘤细胞中的作用是什么？ 肠TRM细胞的分化和维持？什么是TGF-β依赖的转录程序 被肠道TRM细胞中的Eomes阻止的 3)TGF-β依赖性诱导转录因子Runx 3的功能是什么？无论Eomes 和Runx 3共同控制肠道TRM细胞中大部分TGF-β依赖性转录程序？ 这些研究的结果将阐明TGF-β调控的转录程序。 肠TRM细胞的分化和维持。这些研究将大大加深我们对 消化TRM细胞生物学，并为未来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-β 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-β signaling in gut TRM cells. Using different genetic models (conditional and inducible knockout mice that specifically delete TGF-β receptor on T cells, and TGF-β 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-β signaling? Whether continuous TGF-β signaling is required for the maintenance of gut TRM cells? What is the transcription program maintained by TGF-β signaling in gut TRM cells? 2) What is the function of TGF-β-dependent down-regulation of transcription factor Eomes in the differentiation and maintenance of gut TRM cells? What is the TGF-β-dependent transcription program that is prevented by Eomes in gut TRM cells? 3) What are the functions of TGF-β dependent induction of transcription factor Runx3? Whether Eomes and Runx3 together control the majority of TGF-β-dependent transcription program in gut TRM cells? The results from these studies will elucidate the transcription program underlying TGF-β-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.