CD4+ T淋巴细胞内源性CSE/H2S调节免疫检查点在动脉粥样硬化中的作用及机制研究

CD4 T细胞介导的炎症与动脉粥样硬化密切相关。研究表明，H2S具有动脉粥样硬化保护作用。H2S生成关键酶CSE在CD4 T细胞中表达，但是其功能尚不明确。申请人前期工作发现，特异性敲除CD4 T细胞内源性CSE促进动脉粥样硬化，同时，CSE缺失的CD4细胞免疫检查点蛋白细胞毒性T淋巴细胞相关蛋白-4（CTLA-4）下调，促炎细胞因子释放增加。因此，我们推测CD4细胞内源性CSE/H2S通过免疫检查点CTLA-4抑制效应T细胞的免疫过度活性是其动脉粥样硬化保护作用的关键机制。本研究拟通过特异性敲除CD4细胞CSE，并制备动脉粥样硬化模型，观察斑块面积、斑块稳定性、CTLA-4及其配体表达以及T细胞活化水平，进而在细胞水平探讨H2S调控CTLA-4表达的靶点及机制。本研究有助于了解CD4 T细胞内源性CSE/H2S在动脉粥样硬化中的作用，并为动脉粥样硬化的临床治疗提供新的思路和靶点。

CD4+ T cell-mediated inflammation is closely related to atherosclerosis. Studies have shown that H2S has a strong protective effect on atherosclerosis, and its endogenous-generation key enzyme cystathionine γ lyase (CSE) is expressed in CD4+ T cells, but its function remains unclear. Our preliminary data have shown that the CD4+ T cell-specific deletion of CSE accelerated atherosclerosis by increasing inflammatory cytokines, In vitro, CSE-deficient CD4+ T cells also produced an increased level of pro-inflammatory cytokines via a CTLA-4 dependent pathway. Accordingly, we hypothesize CD4+ T cell endogenous CSE/H2S may halt the progression of atherosclerosis by suppressing immune overactivity of effector T cells via CTLA-4 dependent pathway. To test this hypothesis, we aim to establish a model of atherosclerosis in CD4+ T cell CSE knock out mice， evaluate the plaque area, CTLA-4 protein expression, and the level of activated T cells, then determine the mechanisms and target by which CTLA-4 expression and activity are regulated by H2S in CD4+ T cells. Findings from this study will provide insights into the role of CD4+ T cell endogenous CSE/H2S in atherosclerosis and offer novel strategies for the prevention and treatment of atherosclerosis.