胸腺髓质上皮细胞对Treg细胞可塑性的调控及在重症肌无力病损中的作用和机制

Myasthenia gravis (MG) is an autoimmune disease. MG thymus usually displays hyperplasia or thymoma. Infection is a common inducer for MG exacerbation or relapse. Regulatory T cells (Tregs) are most important immunosuppressive cells, and their decrease and dysfunction is common in MG. There is still no report about thymic medullar epithelial cells (mTECs)’ role for thymic CD4+ T cells polarization and function in MG patients. Besides increasing AChR alpha subunit expression, our data showed that poly(I:C) also down regulated inducible T-cell costimulator ligand (ICOSL) expression by mTECs. The supernatant of poly(I:C) treated mTECs lowered FoxP3 expression in thymic CD4+ T cells, indicating dysfunctional Tregs in the thymus. Here we plan to compare toll-like receptor (TLR) and ICOSL expression in thymoma from MG and non-MG patients and correlate these proteins with disease severity. By establishing poly(I:C)-MG mouse model, firstly, we plan to study the effects of poly(I:C) on ICOSL and other cytokines expression/secretion by mTECs and the related signaling pathways; secondly, to study the Tregs polarization, apoptosis and suppressive function when co-cultured (direct or indirect) with poly(I:C) treated mTECs. The above work will mimic the progress of virus infection in MG patients and help us to understand MG thymus pathology and provide the targets of MG therapy.

重症肌无力（MG）是一种自身免疫性疾病，常伴胸腺异常。病毒对胸腺细胞有趋向性感染，为该病常见诱因。Treg是人体最重要的免疫抑制细胞，在MG病损中数量减少并功能紊乱。MG患者胸腺髓质上皮细胞（mTEC）对Treg极化和功能的作用及机制未见报道。我们前期研究发现，poly(I:C)下调mTEC可诱导共刺激分子配体（ICOSL）表达并降低CD4+T细胞的FoxP3水平。本研究拟通过比较MG和普通胸腺瘤的Toll样受体、ICOSL等表达差异及与疾病严重度的关联，建立poly(I:C)实验性MG小鼠模型，开展以下两方面研究：①poly(I:C)对MG小鼠mTEC的蛋白表达的影响及相关信号通路；②经poly(I:C)刺激的mTEC对胸腺Treg的极化、凋亡和抑制功能的影响及相关信号通路。通过上述研究，模拟病毒感染对mTEC功能和胸腺Treg极化作用的影响，为MG发病机制提供新的实验依据和治疗靶点。