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

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.

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。

Treg的免疫抑制性是指经TCR介导的信号刺激活化以后能够抑制CD4+CD25+T细胞的活化和增殖。大量研究表明，Treg不仅在自身耐受的获得和维持及自身免疫的防御中起重要作用，在肿瘤、移植耐受甚至是病原体感染等免疫反应调节中也扮演重要角色。虽然其机制至今还不是十分明确，但大量研究表明Treg细胞的发育、功能的发挥与一个蛋白质分子——Foxp3有着密切的联系。Foxp3是一种转录因子，它能通过调控特定基因的表达，从而控制Treg细胞的分化成熟。我们通过研究CD4+CD25+Treg细胞的FOXP3基因甲基化和表达量的改变，证实了CD4+CD25+Treg的RANTES缺陷是类风湿关节炎（RA）的致病原因之一。CD4+CD25+Treg细胞FOXP3基因的对炎症因子的反应受到RANTES的调控，RA患者炎症刺激下FOXP3没有能完全去甲基化，表达程度受到了抑制，而这个过程能够被外源性RANTES逆转。这一研究揭示了RANTES是通过对FOXP3基因的甲基红调控影响FOXP3基因的表达，从而达到抑制炎症反应的作用。对RA患者的RANTES缺陷进一步研究将有助于为RA的治疗提供新的治疗靶点。