HBV特异性细胞毒T细胞（CTL）是决定HBV感染转归的关键因素，其功能受损或耗竭与乙肝慢性化密切相关。iTR35是调节性T细胞新成员，通过分泌IL-35发挥免疫抑制功能，而核基质蛋白SATB1可诱导调节性T细胞转化使其失去免疫抑制效应。我们前期研究发现IL-35可明显抑制HBV特异性CTL功能而致其耗竭，但机制不明。本项目从iTR35分泌IL-35并经JAK/STAT通路引发HBV特异性CTL耗竭、SATB1诱导iTR35转化而阻断CTL耗竭的思路出发，首先了解慢性乙肝患者iTR35和HBV特异性CTL功能及其相互关系，进而探明iTR35经上述通路抑制CTL增殖及上调耗竭分子或下调效应分子表达、SATB1干预iTR35表达IL-35而使其丧失抑制CTL功能、输入SATB1过表达iTR35能终止小鼠HBV持续感染的作用及其分子机制，为未来进一步发展以SATB1为靶点的乙肝治疗新药奠定基础。

Hepatitis B virus (HBV) specific cytotoxic T lymphocytes (CTL) is a key factor in determining the outcome of HBV infection, its functional impairment or exhaustion are closely related to chronic hepatitis. Interleukin-35 (IL-35) induced regulatory T cells (iTR35) are new members of regulatory T cells, which exert immunosuppressive function by secretion of IL-35, meanwhile, special AT rich sequence binding protein 1 (SATB1) can induce regulatory T cell transformation and therefore lose their immunosuppressive effect. Our previous study demonstrated that IL-35 can inhibit the function of HBV-specific CTL and induce their exhaustion, however, the mechanism is unknown. This project aims to investigate from the aspects including the secretion of IL-35 by iTR35 via JAK/STAT pathway to trigger HBV-specific CTL exhaustion, SATB1 induced iTR35 conversion and block CTL exhaustion. Our expected results will firstly understand the function of iTR35 and HBV-specific CTL of chronic hepatitis B patients as well as their relationship, and then explore the mechanism of how iTR35 cells inhibit CTL proliferation, up-regulate the expression of exhaustion molecules and down-regulate effector molecules through this way. SATB1 intervention can inhibit iTR35 cells to express IL-35 and lose their inhibition function to CTL, and the transfer of SATB1-overexpressed iTR35 in mice are able to terminate the development of HBV persistent infection, which provides research foundation for new drugs targeting SATB1 to treat hepatitis B patients.