Generation and Immune Regulation of CD4+CD25-Foxp3+ T Cells in Chronic Obstructive Pulmonary Disease
Generation and Immune Regulation of CD4+CD25-Foxp3+ T Cells in Chronic Obstructive Pulmonary Disease
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慢性阻塞性肺疾病中 CD4( )CD25(-)Foxp3( ) T 细胞的生成和免疫调节。
DOI：
10.3389/fimmu.2019.00220
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发表时间：
2019-02-20
影响因子：
7.3
通讯作者：
Tao, Xiao-Nan
中科院分区：
文献类型：
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作者：
Wu, Jiang-Hua;Zhou, Mei;Tao, Xiao-Nan
慢性阻塞性肺疾病(COPD)患者的炎性免疫反应异常与CD4+Foxp3+T细胞亚群失衡有关。然而，CD41-CD25-Foxp3+T细胞在COPD免疫调节中的可能作用仍有待研究。本研究采用流式细胞术检测外周血中CD4+CD25-Foxp3+T细胞的分布和表型特征，并在体外进一步探讨其来源、免疫功能和最终归宿。观察到稳定期COPD患者外周血中CD4+CD25-Foxp3+T细胞明显升高，类似于中枢记忆T细胞或效应记忆T细胞。与外周血中的CD4+CD25-Foxp3+T细胞相比，外周血中Foxp3的表达明显降低。CTLA-4、HELIOS、TIGIT表达增强，CD127、Ki-67表达增强，提示随着CD25表达降低，CD4+CD25-Foxp3+T细胞失去了Tregs相关分子的表达。出乎意料的是，我们的研究发现，转化生长因子1)降低了CD25的表达，并在由CD4+CD25+Foxp3+T细胞产生CD4+CD25-Foxp3+T细胞过程中发挥了关键作用。表型分析进一步显示，可诱导的和外周血中的CD4+CD25-Foxp3+T细胞都具有激活的常规T细胞的特征。重要的是，记忆CD41-CD25-Foxp31-T细胞在IL-113、IL-6、IL-23和TGFO的存在下，促进了初始的CD4+T细胞的增殖和分化为Th17细胞。最后，一部分表现出不稳定性和可塑性的CD4+CD25-Foxp3+T细胞在Th17细胞极化条件下转化为Th17细胞。综上所述，我们认为TGF11负责CD4+CD25-Foxp3+T细胞的产生，这些细胞在功能上对Th17细胞的产生起辅助作用，并可能持续COPD的慢性炎症。
The imbalance of CD4+Foxp3+ T cell subsets is reportedly involved in abnormal inflammatory immune responses in patients with chronic obstructive pulmonary disease (COPD). However, the possible role of CD41-CD25-Foxp3+ T cells in immune regulation in COPD remains to be investigated. In the current study, distribution and phenotypic characteristics of CD4+CD25-Foxp3+ T cells from peripheral blood were determined by flow cytometry; the origin, immune function and ultimate fate of CD4+CD25-Foxp3+ T cells were further explored in vitro. It was observed that circulating CD4+CD25-Foxp3+ T cells were significantly increased in stable COPD patients (SCOPD) and resembled central memory or effector memory T cells. Compared with peripheral CD4+CD25 Foxp3+ T cells, peripheral CD4+CD25-Foxp3+ T cells showed a lower expression of Foxp3. CTLA-4, HELIOS, and TIGIT, but a higher expression of CD127 and KI-67, suggesting that CD4+CD25-Foxp3+ T cells lost the expression of Tregs-associated molecules following the reduction in CD25. Unexpectedly, our study found that transforming growth factopri (TGF1))1) decreased CD25 expression and played a critical role in the generation of CD4+CD25-Foxp3+ T cells from CD4+CD25+Foxp3+ T cells. Phenotypic analysis further revealed that both inducible and peripheral CD4+CD25-Foxp3+ T cells exhibited the features of activated conventional T cells. Importantly, memory CD41-CD25-Foxp31-T cells facilitated the proliferation and differentiation of naive CD4+ T cells into Th17 cells in the presence of IL-113, IL-6, IL-23, and TGFO. Finally, a fraction of CD4+CD25-Foxp3+ T cells, exhibiting instability and plasticity, were converted to Th17 cells when subjected to Th17 cell-polarizing condition. Taken together, we propose that TGF11 is responsible for the generation of CD4+CD25-Foxp3+ T cells, and these cells functionally exert an auxiliary effect on Th17 cells generation and might perpetuate chronic inflammation in COPD.