香烟烟雾暴露对调节性T细胞糖蛋白A主导重复序列（GARP)表达的影响及其机制研究

The functional or frequency deficiency of the regulatory T cells (Tregs) plays an important role in autoimmunity of COPD.Recent studies revealed that a transmembrane protein called glycoprotein A repetitions predominant (GARP, or LRRC32)is the most specific functional marker of activated Treg cell.Our previous study found that the expression of GARP on peripheral regulatory T cells decreased whereas the IL-17 producing Foxp3+ T cells significantly increased in COPD patients.Epigenetic regulation including histone acetylation and cytosine residue methylation has been reported to regulate the expression fo Foxp3 gene. However, the modulation mechanism of GARP gene remains unclear.Thus we suppose that epigenetic regulation may control the expression of GARP. To test this hypothesis, we intend to perform in vitro and in vivo experiments to investigate the circulation and pulmonary GARP expression in COPD patients. Moreover, we will clarify whether cigrette smoking exposure could influence the GARP expression by modulating HDAC activity and methylation status of CpG dinucleotides at the GARP locus which is associated with activation of PI3K. Our study would elucidate the influence of environment factors on immune regulation function and promote clinic immune therapy research for COPD.

调节性T细胞（Treg）的数量和或功能的改变在COPD自身免疫的发生中起关键作用。新近的研究表明，糖蛋白A主导重复序列（GARP）是活化Treg细胞表达的具有高度特异性并与功能相关的标记分子。我们的前期研究首次发现COPD患者外周血中GARP的表达下降，分泌IL-17的Foxp3+细胞显著增高,机制不明；但我们推测这些改变可能与香烟烟雾暴露有关。有研究发现DNA的甲基化和HDAC活性改变等调节机制能够调控Treg细胞Foxp3基因的表达。据此提出本课题：1）COPD患者循环和肺局部存在GARP表达的改变；2）通过烟草提取物（CSE）体外干预实验及COPD模型来证实，香烟烟雾暴露可能通过激活PI3K从而改变HDAC活性以及GARP基因的CPG甲基化来影响GARP的表达。研究结果有助于阐明环境因素对免疫调节机能的影响及其机制，为COPD免疫调节治疗寻找新的靶点。