WAVE2调控SATB1促进Tfh细胞分化在系统性红斑狼疮发病机制中的研究

Tfh cells differentiation plays an important role in the development of systemic lupus erythematosus (SLE). However, the mechanism underlying the regulation of Tfh cells differentiation in SLE is not clear. Our previous study found reduced expression of WAVE2 in the CD4+ T cells of SLE patients. The CD4+ T cells specific WAVE2 (WAVE2-/-) knockout mice also showed increased Tfh cells differentiation and SLE manifestations. In addition, we found WAVE2 was accumulated in the nucleus of CD4+ T cells in Tfh polarization condition. RNA-Seq, ChIP, Co-IP and Mass spectrometry indicated WAVE2 might form a complex with Pol II and RbBP5, the complex binded the promoter of SATB1, which controlled the Tfh cells differentiation through ICOS/PI3K/Akt pathway. Thus, we hypothesize that reduced expression of WAVE2 may decrease the expression of SATB1 and activated the ICOS/PI3K/Akt pathway, accelerate the Tfh cells differentiation and development of SLE. This study aims to elucidate the mechanism about how WAVE2 regulate the transcription of SATB1 and the differentiation of Tfh cells in SLE, which will shed light on the pathogenesis and clinical treatment of SLE.

Tfh细胞分化在SLE的发生发展中发挥重要作用，但其调控机制仍有待进一步阐明。我们前期预实验发现SLE患者CD4+T淋巴细胞中WAVE2表达显著降低，条件性CD4+T淋巴细胞WAVE2-/-小鼠出现CD4+T淋巴细胞向Tfh分化增多及SLE的发生。并且体外刺激 CD4+T淋巴细胞Tfh分化发现WAVE2入核，RNA-seq, ChIP, Co-IP及质谱分析提示核内WAVE2可能与Pol II，RbBP5形成复合体与SATB1启动子区结合, 调控ICOS/PI3K/Akt通路及Tfh分化。因此，我们推测：WAVE2表达降低/缺失可能通过下调SATB1的转录表达激活ICOS/PI3K/Akt通路，从而促进Tfh分化及SLE的发生。本研究拟通过体内、体外实验研究WAVE2调控SATB1转录表达的分子机制及其调控Tfh分化与SLE的关系，为揭示SLE的发病机制及临床治疗提供新的思路和方向。

Tfh的异常分化和激活在SLE的发生发展中发挥重要作用，但调控 Tfh分化的分子机制及其在 SLE 发生和发展中的关系，目前尚不十分清楚。我们前期预实验发现SLE患者CD4+T淋巴细胞中WAVE2表达显著降低，条件性CD4+T淋巴细胞WAVE2-/-小鼠出现CD4+T淋巴细胞向Tfh分化增多及SLE的发生。并且体外刺激 CD4+T淋巴细胞Tfh分化发现WAVE2入核，RNA-seq, ChIP, Co-IP及质谱分析提示核内WAVE2可能与Pol II，RbBP5形成复合体与SATB1启动子区结合, 调控Tfh分化。本研究拟通过体内、体外实验研究WAVE2调控SATB1转录表达的分子机制及其调控Tfh分化与SLE的关系，为揭示SLE的发病机制及临床治疗提供新的思路和方向。. 针对以上科学问题，本项目按照研究计划，取得如下发现：1、WAVW2在SLE患者中表达明显降低；2、WAVE2缺失导致T细胞发育、增值、凋亡、移动、黏附等功能异常；3、WAVE2可以入核并与Sral，Nap1，Abi1和HSPC300形成复合物；4、核内WAVE2可以与RbBP5结合。5、WAVE2表达缺失／降低促进CD4+T淋巴细胞向Tfh分化。以上研究提示：WAVE2可能通过入核结合RbBP5，并调控Tfh细胞分化，从而参与SLE的发生发展机制。