Decreased frequencies and impaired functions of the CD31+ subpopulation in Treg cells associated with decreased FoxP3 expression and enhanced Treg cell defects in patients with coronary heart disease
Decreased frequencies and impaired functions of the CD31+ subpopulation in Treg cells associated with decreased FoxP3 expression and enhanced Treg cell defects in patients with coronary heart disease
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冠心病患者 T-reg 细胞中 CD31 亚群的频率降低和功能受损与 FoxP(3) 表达降低和 T-reg 细胞缺陷增强相关
DOI：
10.1111/cei.12897
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发表时间：
2017-03-01
影响因子：
4.6
通讯作者：
Shen, L.
中科院分区：
文献类型：
--
作者：
Huang, L.;Zheng, Y.;Shen, L.
冠心病（冠心病）是动脉粥样硬化引起的最常见的脏器病变之一，其中CD4+CD25+叉头盒蛋白3 （FoxP3+）调节性T细胞（Treg）发挥动脉粥样硬化保护作用。然而，动脉粥样硬化中Treg细胞数量减少，功能受损；其潜在机制尚不清楚。CD31在T细胞应答中起重要作用，并有助于维持T细胞的耐受性。CD31的免疫调节作用也与动脉粥样硬化有关。在本研究中，我们发现冠心病患者Treg细胞（CD31+Tr细胞）中CD31+亚群频率的降低与FoxP3表达的降低呈正相关。体外细胞培养表明，与Treg细胞（CD31 - Tr细胞）中的CD31 -亚群相比，CD31+Tr细胞在激活后保持稳定的FoxP3表达，并表现出增强的增殖和免疫抑制。我们还证实了冠心病患者CD31+Tr细胞中转化生长因子（TGF）‐β1和白细胞介素（IL）‐10的分泌受损。进一步分析发现，冠心病患者CD31+Tr细胞中磷酸化- SHP2（与CD31激活相关）和磷酸化-信号转换器和转录激活因子- 5（与FoxP3转录相关）水平降低，提示CD31+Tr细胞中FoxP3表达降低可能是由于SHP2和STAT - 5激活减弱。这些数据表明，与FoxP3表达减少相关的CD31+Tr亚群频率降低和功能受损，至少在一定程度上导致冠心病患者Treg细胞缺陷。我们的研究结果强调了CD31+Tr亚群在维持Treg细胞正常功能中的重要作用，并可能为冠心病中Treg细胞免疫调节受损提供新的解释。
Coronary heart disease (CHD) is one of the most common types of organ lesions caused by atherosclerosis, in which CD4+CD25+forkhead box protein 3 (FoxP3+) regulatory T cells (Treg) play an atheroprotective role. However, Treg cell numbers are decreased and their functions are impaired in atherosclerosis; the underlying mechanisms remain unclear. CD31 plays an important part in T cell response and contributes to maintaining T cell tolerance. The immunomodulatory effects of CD31 are also implicated in atherosclerosis. In this study, we found that decreased frequencies of the CD31+ subpopulation in Treg cells (CD31+Tr cells) correlated positively with decreased FoxP3 expression in CHD patients. Cell culture in vitro demonstrated CD31+Tr cells maintaining stable FoxP3 expression after activation and exhibited enhanced proliferation and immunosuppression compared with the CD31− subpopulation in Treg cells (CD31−Tr cells). We also confirmed impaired secretion of transforming growth factor (TGF)‐β1 and interleukin (IL)‐10 in CD31+Tr cells of CHD patients. Further analysis revealed reduced phospho‐SHP2 (associated with CD31 activation) and phospho‐signal transducer and activator of transcription‐5 (STAT‐5) (associated with FoxP3 transcription) levels in CD31+Tr cells of CHD patients, suggesting that decreased FoxP3 expression in CD31+Tr cells might be because of attenuated SHP2 and STAT‐5 activation. These data indicate that decreased frequencies and impaired functions of the CD31+Tr subpopulation associated with decreased FoxP3 expression give rise, at least in part, to Treg cell defects in CHD patients. Our findings emphasize the important role of the CD31+Tr subpopulation in maintaining Treg cell normal function and may provide a novel explanation for impaired immunoregulation of Treg cells in CHD.