内皮细胞PD-L1抑制诱导T细胞活化参与动脉粥样硬化的机制

动脉粥样硬化(AS)是血管慢性炎症性疾病，以免疫活化为特征。内皮细胞(ECs)功能异常是触发血管炎症反应的重要因素。程序性细胞死亡蛋白配体-1(PD-L1)负性调控T细胞活化。我们前期研究发现：AS时，病变血管PD-L1表达改变与CD4+T浸润存在关联；内皮细胞PD-L1抑制诱导CD4+T活化迁移；TNF-α通过NF-κB调控内皮细胞PD-L1表达。我们假设：AS时，在TNF-α/PGC-1α/NF-κB通路调控下，内皮细胞PD-L1表达下降，阻断与T细胞表面PD-1受体结合，拮抗PD-1/PD-L1途径对T细胞活化的负性调控，诱导T细胞活化释放IFN-γ，在IFN-γ刺激下巨噬细胞吞噬脂质形成泡沫样细胞，加重AS。本课题从内皮细胞调控T细胞活化的新角度，阐明T细胞活化参与AS的新机制，为AS的临床治疗提供新思路，也为阐明肿瘤免疫治疗中使用的抗PD-L1单抗诱发血管毒性的机制提供理论依据。

Atherosclerosis(AS) is a chronic inflammation disease that are markedly correlated with inflammation and immune reactions. Endothelial cells morphology and function abnormal is the reason that associate with immune responses. Programmed death ligand-1(PD-L1) on antigen-presenting cells(APCs) interact with PD-1 on T cells, and has been demonstrated to play a role in the negative regulation of immune responses and peripheral tolerance. Our previous studies found that the alteration of PD-L1 level in artery was associated with the infiltration of CD4+T cells in AS model; down-regulated the expression of PD-L1 induce the activition and migration of CD4+T cells; TNF-α regulated the expression of PD-L1 in ECs through NF-κB. Therefore we hypothesize that TNF-α through PGC-1α/NF-κB signaling pathway down-regulate the expression of PD-L1 in ECs, then impede the interaction between PD-L1 and PD-1 that lead to the shut of T cells activity. The activation of T cells release the IFN-γ that is closely related to the activation of macrophage and stimualte the macrophage swallow lipid to formate the foam cells, then aggravate the AS. This study provides novel mechanism expanding the activation of T cells to the regulation of Atherosclerosis, thereby suggesting a novel therapeutic indication for PD-L1 modulation. The present study contributed to the understanding of the roles of T cells in the vascular disease and the mechanism of the abnormal immune/inflammatory response in AS. The understanding of immune response will put forward new sight to avoid the toxicity which induce by anti-PD-L1 antibody in clinical.