SLE患者NKG2D+CD4+T细胞杀伤调节性T细胞及分子机制研究

Regulatory T cells (Tregs) play a pivotal role in miantianing immunological homeostasis. Cytotoxic T cells can induced Treg cells to decreased. Our preliminary research found that the Tregs could be killed by NKG2D+CD4+T effectively in vitro. However, the detailed mechanisms for the cytolysis of Treg cells by NKG2D+CD4+ T cells all remain unknown. Therefore, in this study, based on the preliminary results in our lab, we will further investigate whether the aberrantly increased TNFα in SLE serum could bind to the cognate receptor TNFR on Tregs, and then activate the NF-κB pathway and accompany with the decreased DND methylation in the CpG islands within ULBP1-3 genes, up-regulating the expression of ULBP1-3 genes. We also clarify the details mechanisms by which NKG2D+CD4+ T cells kill ULBP+Treg cells. The expected results in this study will be valuable by adding novel details for the mechanisms of SLE pathogenesis and provide the potential intervening targets for immunotherapy of SLE.

调节性T细胞（Treg）功能障碍是系统性红斑狼疮（SLE）自身免疫形成的重要机制，细胞毒性T细胞是引发Treg细胞减少的基本因素。课题组前期研究结果证实，CD4+NKG2D+T细胞可有效裂解Treg细胞，但分子机制并不清楚。为探讨CD4+NKG2D+T细胞引发Treg细胞减少的机制，本课题拟了解SLE患者血清诱导Treg细胞上调NKG2D配体（NKG2DLS）表达水平，在此基础上分别从转录和表观遗传学角度探讨TNFɑ诱导Treg细胞表达ULBPs分子及调控机制，以探讨CD4+NKG2D+T细胞杀伤Treg细胞机制，为SLE的发病机制提供全新的理论，并为生物治疗提供新的靶点。

Tregs在维持免疫自稳中起关键作用。我们前期实验发现SLE患者体内Tregs显著减少，但N KG2D+CD4+T细胞显著增高，两者呈负相关；SLE血清和Tregs中TNFα和TNFR分别显著升高；SLE 血清刺激正常Tregs高表达NKG2D配体ULBP1-3，后者可被NKG2D+CD4+T细胞有效杀伤。但SLE血 清如何诱导Tregs表达ULBPs以及ULBPs+Tregs如何被NKG2D+CD4+T细胞杀伤的机制未知。针对这 些问题，我们通过该项目的研究，得知SLE患者异常升高的TNFα与Tregs上TNFR结合后 ，激活NF-κB通路并降低ULBP1-3基因的CpG岛DNA甲基化，从而上调ULBP1-3表达；同时剖析NK G2D+CD4+T细胞具体的杀伤分子机制。结果阐明SLE的新发病机制并为其治疗提供新的潜在干 预靶点。