Tai Ping, Wang Junpeng, Jin Huali, Song Xiaoming, Yan Jun, Kang Youmin, Zhao Lin, An Xiaojin, Du Xiaogang, Chen Xiufen, Wang Songbo, Xia Guoliang, Wang Bin
State Key Laboratories of Agro-biotechnology, College of Biological Science, China Agricultural University, Beijing, People's Republic of China.
J Cell Physiol. 2008 Feb;214(2):456-64. doi: 10.1002/jcp.21221.
Naturally occurring CD4+CD25+ regulatory T cells (Treg) exert an important role in mediating maternal tolerance to the fetus during pregnancy, and this effect might be regulated via maternal estrogen secretion. Although estrogen concentration in the pharmaceutical range has been shown to drive expansion of CD4+CD25+ Treg cells, little is known about how and through what mechanisms E2 within the physiological concentration range of pregnancy affects this expansion. Using in vivo and in vitro mouse models in these experiments, we observed that E2 at physiological doses not only expanded Treg cell in different tissues but also increased expression of the Foxp3 gene, a hallmark for CD4+CD25+ Treg cell function, and the IL-10 gene as well. Importantly, our results demonstrate that E2, at physiological doses, stimulated the conversion of CD4+CD25- T cells into CD4+CD25+ T cells which exhibited enhanced Foxp3 and IL-10 expression in vitro. Such converted CD4+CD25+ T cells had similar regulatory function as naturally occurring Treg cells, as demonstrated by their ability to suppress naïve T cell proliferation in a mixed lymphocyte reaction. We also found that the estrogen receptor (ER) exist in the CD4+CD25- T cells and the conversion of CD4+CD25- T cells into CD4+CD25+ T cells stimulated by E2 could be inhibited by ICI182,780, a specific inhibitor of ER(s). This supports that E2 may directly act on CD4+CD25- T cells via ER(s). We conclude that E2 is a potential physiological regulatory factor for the peripheral development of CD4+CD25+ Treg cells during the implantation period in mice.
天然存在的CD4+CD25+调节性T细胞（Treg）在孕期介导母体对胎儿的耐受性中发挥重要作用，且这种作用可能通过母体雌激素分泌来调节。尽管已表明药物剂量范围内的雌激素浓度可促使CD4+CD25+ Treg细胞扩增，但对于孕期生理浓度范围内的E2如何以及通过何种机制影响这种扩增却知之甚少。在这些实验中，我们使用体内和体外小鼠模型观察到，生理剂量的E2不仅能使不同组织中的Treg细胞扩增，还能增加Foxp3基因（CD4+CD25+ Treg细胞功能的标志）以及IL-10基因的表达。重要的是，我们的结果表明，生理剂量的E2在体外刺激CD4+CD25- T细胞转化为CD4+CD25+ T细胞，这些细胞表现出增强的Foxp3和IL-10表达。如在混合淋巴细胞反应中抑制幼稚T细胞增殖的能力所示，这种转化后的CD4+CD25+ T细胞具有与天然存在的Treg细胞相似的调节功能。我们还发现雌激素受体（ER）存在于CD4+CD25- T细胞中，且E2刺激的CD4+CD25- T细胞向CD4+CD25+ T细胞的转化可被ER特异性抑制剂ICI182,780抑制。这支持E2可能通过ER直接作用于CD4+CD25- T细胞。我们得出结论，E2是小鼠着床期CD4+CD25+ Treg细胞外周发育的潜在生理调节因子。
