系统性硬化病(SSc)是一种以炎症和纤维化为主的结缔组织病（CTD），T淋巴细胞发挥重要的作用。IL-35是一种免疫抑制因子，能诱导初始T细胞转变成一种强抑制性的调节性T细胞(iTr35)，分泌成熟IL-35发挥强大免疫抑制作用，形成正反馈调节。研究认为IL-35在CTD中发挥了重要作用。我们前期研究显示，SSc患者及小鼠模型外周血和肺、皮肤组织中IL-35表达增高，Treg细胞功能异常，Th17细胞数量增加，与纤维化病变程度相关。SSc患者体内，IL-35是否可诱导CD4+T细胞分化成iTr35细胞，调节Treg/Th17细胞的平衡，发挥免疫抑制功能有待于进一步研究。本项目采用体外细胞培养、分子生物学和小鼠模型等方法，研究SSc中IL-35诱导CD4+T淋巴细胞分化为iTr35的分子机制，及其对Treg/Th17细胞失衡和成纤维细胞功能的影响，阐明IL-35和iTr35在SSc中的作用。

Systemic sclerosis (SSc) is a type of autoimmune disease, characterized by immune system abnormalities as well as fibrosis of the skin and internal organs. However, its etiology is not completely understood. T lymphocytes are known to play an important role in the process of the disease. Interleukin(IL)-35 is a novel immune-suppressive cytokine, which can induce naive T cell to differentiate into a regulatory T-cell(Treg) population, called iTr35 that produces mature IL-35 and strongly suppresses inflammation，which positive feedback regulation was formed. Recent studies showing IL-35 was involved in the immunopathogenesis of CTD. Our previous research demonstrated that the increased level of IL-35 in SSc patient’s peripheral blood, the elevated expansion of the Th17 cell population, the changed number and/or defective suppressive function of Treg cells in SSc patients and animal models, which were correlated with the fibrotic lesions. However, whether IL-35 can induce CD4+ T lymphocytes differentiate to iTr35 cell and affect the balance Teff/Treg cell, to suppress immune in SSc patients, are still need to further study. The primary aim of this project is to explore the molecular mechanism how IL-35 induce CD4+ T lymphocytes differentiate to iTr35 cell, and find out the regulatory role of iTr35 on Teff/Treg cell balance and the effect on fibroblast function in patients with SSc. This study would further elucidate the role of IL-35 and iTr35 cells in the pathogenesis of SSc, and provide a valuable information of biological target therapy.