RANTES在类风湿关节炎CD4+CD25+Treg细胞Foxp3启动子区甲基化中的调控机制

CD4+CD25+Treg细胞表达RANTES受体，转录因子Foxp3的表遗传学修饰与CD4+CD25+调节性T细胞功能有密切的联系。我们研究发现类风湿关节炎CD4+CD25+Treg细胞功能存在缺陷。实验显示具有稳定功能的CD4+CD25+Treg细胞，是由Foxp3的表遗传学的修饰来完成的。通过研究RA患者与正常人整体基因甲基化的差异，RA患者CD4+CD25+Treg细胞的组蛋白密码子修饰与正常人的差异，进一步研究正常人和RA患者Foxp3启动子区甲基化的不同；RNAi沉默CD4+CD25+Treg细胞RANTES表达，分析在RA中高度表达的T细胞趋化因子RANTES与Foxp3甲基化水平的关系。通过本研究，将阐明RANTES在类风湿关节炎CD4+CD25+Treg细胞Foxp3启动子区甲基化中的作用机制，从而针对此机制设计出有效的干预手段。

Naturally occurring thymus derived regulatory T cells (Tregs) are central in the maintenance of self-tolerance.The transcription factor FOXP3 is crucial for the suppressive activity of Tregs and is considered the most specific marker for this population. However, human non regulatory T cells upregulate FOXP3 transiently upon activation which calls for other means to identify the Treg population. Since epigenetic mechanisms are involved in the establishment of stable gene expression patterns during cell differentiation, we hypothesized that the methylation profile of the FOXP3 promoter would allow the distinction of truly committed Tregs.We before discovered the defect of CD4+CD25+Tregs in RA patients.Human CD4+CD25+ Tregs displayed a demethylated FOXP3 promoter in contrast to CD4+CD25lo T cells which were partially methylated.We study differences of modification in histone cordon between RA patients and control group.We silence the RANTES expression in CD4+cd25+Treg by RNAi.Furthermore we will anlalysie the relationship of RANTES and the level of Foxp3 methylation.We will also clarify the mechanism how RANTES acts on the Foxp3 promoter methylation in CD4+CD25+Treg.