CD11a协同Syk调控Th17细胞分化的机制研究

Multiple sclerosis (MS) is the most common autoimmune disease in the central nervous system. Chronic focal demyelination and neurodegeneration are the main pathological features, while Th17 cells play a prominent role in the process of demyelination. CD11a is highly expressed on the surface of T lymphocytes and participates in T cell proliferation and apoptosis. However, the effect of CD11a on T cell differentiation is still unclear. In previous study, we found that CD11a expression levels were negatively correlated with disease severity in tissue samples from patients with multiple sclerosis and mice with autoimmune meningitis. CD11a deletion and overexpression in T cells confirmed that CD11a specifically inhibited Th17 cell polarization, which is associated with Syk-mediated phosphorylation of STAT1 at Tyr701 site. Plasmid co-transfection experiments found that CD11a directly promoted Syk activation. Hence, we hypothesized that CD11a may act a pivotal part in negatively regulating the differentiation of Th17 cells by cooperating with Syk to promote STAT1 phosphorylation. This study aims to explore the specific mechanism of CD11a regulating Th17 cell differentiation from the tissue, cellular and molecular levels, in order to provide a new basis for targeted therapy of multiple sclerosis.

多发性硬化症是中枢神经系统最常见的自身免疫性疾病，以慢性局灶性脱髓鞘和神经变性为主要发病特征，脱髓鞘过程中Th17细胞发挥重要作用。CD11a在T淋巴细胞表面高表达，参与细胞增殖、凋亡等过程，但CD11a对T细胞分化的影响尚不清楚。前期我们发现在多发性硬化症患者和自身免疫性脑脊髓膜炎小鼠的组织样本中，CD11a的表达水平与疾病严重程度呈负性相关。在T细胞中进行CD11a敲除和过表达，研究结果发现CD11a特异性抑制T细胞向Th17细胞极化。其发生机制与Syk介导的STAT1在酪氨酸701位点的磷酸化水平变化有关。质粒共转染实验发现CD11a可直接促进Syk活化。因此我们猜想CD11a可能是通过协同Syk促进STAT1磷酸化进而发挥负向调控Th17细胞分化的作用。本研究将从组织、细胞、分子几个层面深入探讨CD11a调控Th17细胞分化过程的具体机制，为多发性硬化症的靶向治疗提供新依据。

多发性硬化症是中枢神经系统最常见的自身免疫性疾病，以慢性局灶性脱髓鞘和神经变性为主要发病特征，脱髓鞘过程中Th17细胞发挥重要作用。CD11a在T淋巴细胞表面高表达，参与细胞增殖、凋亡等过程，但CD11a对T细胞分化的影响尚不清楚。本项目前期发现，CD11a在多发性硬化症患者组织样本中的表达水平与疾病严重程度呈负性相关。为靶向研究CD11a在CD4+T细胞中的作用，我们使用Cre-loxp系统获得在CD4+T细胞中特异性敲除CD11a的小鼠，同时利用pMX逆转录病毒包装体系实现在原代CD4+T细胞中过表达CD11a。利用T细胞过继回输构建小鼠自身免疫性脑脊髓膜炎（EAE）模型，发现回输CD11a敲除T细胞的实验小鼠EAE发病加重。结合体外T细胞诱导分化及体内EAE模型结果分析发现，CD11a缺失的T细胞可正常活化增殖，在T细胞亚型极化过程中CD11a显著抑制Th17细胞分化。机制研究发现，在诱导Th17细胞分化的IL-6信号刺激下，CD11a缺失的CD4+T细胞中STAT1在酪氨酸701位点的磷酸化水平降低。使用STAT1靶向抑制剂及基因敲除小鼠，证实敲除STAT1可逆转CD11a对Th17细胞分化的抑制作用。综上，本项目研究阐释了CD11a通过调控STAT1磷酸化抑制Th17细胞分化的重要作用，揭示了一种机体维持自身免疫稳态的全新机制，有望为多发性硬化症的靶向治疗提供新依据。