自噬在T细胞发育和Th细胞分化及稳定性作用机制的研究

项目名称： 自噬在T细胞发育和Th细胞分化及稳定性作用机制的研究

项目编号： No.31470861

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 张福萍

作者单位： 中国科学院微生物研究所

项目金额： 85万元

中文摘要： 自噬影响着天然免疫和适应性免疫的很多方面。虽然自噬在天然免疫中的研究取得了很多成就，但在适应性免疫中的作用还有待进一步研究。据此，利用自噬条件性敲除小鼠，研究自噬基因Atg16L1在多个方面对于T细胞稳态和辅助性T细胞亚群分化和维持的影响有非常重要的意义。首先通过将Atg16L1基因条件性敲除的小鼠（Atg16L1f/f）和在T细胞发育不同阶段表达Cre酶的小鼠交配，分析Atg16L1基因在T细胞发育中的作用；其次，通过可诱导性敲除（ATG16L1f/f/ER-T2-Cre)小鼠,研究自噬对辅助性T细胞分化的影响；最后，将重点研究Atg16L1或自噬在维持特定辅助性T细胞亚群Th17和Treg细胞稳定性中的作用和机制。本项目将以独特的角度揭示自噬中的一个未知领域，不仅能更全面的了解适应性免疫，而且将为发展治疗多种与自噬相关疾病的方法提供有利的依据。

中文关键词： 自噬；T细胞发育；T细胞分化

英文摘要： Autophagy influences many aspects of innate and adaptive immunity. Autophagy adjusts cellular biomass and function in response to diverse stimuli, including infection. Autophagy plays specific roles in shaping immune system development, fueling host innate and adaptive immune responses. Although great progress has been made in understanding of autophagy in innate immunity in last decades, only early progress has been made in understanding the roles of autophagy in adaptive immunity, this area warrants more study. Some of the questions that have recently been asked in this area include: the role of autophagy in the polarization of TH17 cells and possibly other T cell subsets, along with the role of autophagy in general lymphocyte homeostasis and differentiation. In this proposal, we propose to address the effect of autophagy gene ATG16L1 on T cell homeostasis and T helper cell subset differentiation in a comprehensive fashion. By cross ATG16L1f/f conditional knock out mice with different Cre mice, we will analyze the effect of ATG16L1 on T cell development, determine whether ATG16L1 involves regulating T helper cell subset differentiation. In order to investigate if ATG16L1 regulate T helper cell lineage commitment, ATG16L1 will delete only after Th17 cell differentiation by crossing the ATG16L1f/f mice with Th17 specific Cre mice. Further study will performed with this mouse to investigate if ATG16L1 play a role in maintenance of Th17 cell stability and function. Finally, the mechanism of ATG16L1 regulates T cell homeostasis and T helper cell differentiation will be investigated. We believe autophagy and immunity are fully integrated, and our continuing study of the interface between these processes will be a fruitful area of sci-entific inquiry for many years to come. We believe our project will provide novel insight into an unexplored area of autophagy biology that will not only fuel a better understanding of adaptive immunity, but will facilitate the development of novel approaches to therapeutic manipulate autophagy.

英文关键词： autophagy;T cell development;T cell differentiation