State Key Laboratory for Agro-Biotechnology, College of Biological Science, China Agricultural University, Beijing 100193, China.
Endocrinology. 2010 Nov;151(11):5477-88. doi: 10.1210/en.2010-0426. Epub 2010 Sep 15.
Mechanisms maintaining the growth of a "semi-foreign" fetus within the maternal uterus via immune tolerance remain unclear. CD4(+)CD25(+) regulatory T (Treg) cells have been implicated in the maintenance of maternal-fetal immune tolerance. Additionally, 17β-estradiol (E2) is able to initiate immune suppression through CD4(+)CD25(+) Treg cells during early pregnancy. Little is known, however, regarding the relationship between progesterone (P4) and immune tolerance during midterm pregnancy, an important period, characterized by higher levels of P4 but lower levels of E2 in the serum. Here, we examined the effects of P4 on the expansion and function of systemic and local uterine CD4(+)CD25(+) Treg cells during midterm pregnancy in mice. Using in vivo and in vitro models, we provide the first evidence that P4 not only increases the proportion of CD4(+)CD25(+) Treg cells and IL-10 expression but also enhances their suppressive function. Moreover, at physiological doses relevant to midterm pregnancy, P4, but not E2, converts CD4(+)CD25(-) T cells into CD4(+)CD25(+) Treg cells. This conversion was inhibited in vitro by the nuclear P4 receptors antagonist RU 486 and in vivo in P4-treated ovariectomized and pseudopregnant mice models, suggesting that P4 expands Treg populations via nuclear P4 receptors. Furthermore, RU 486 significantly reduced the quantity and function of Treg cells in the fetal-maternal interface before the onset of induced abortion. Interestingly, with decreasing Foxp3, proinflammatory factors increased. Together, the present results demonstrate that P4 is an important regulator of systemic and local CD4(+)CD25(+) Treg cells, which are involved in maintaining maternal-fetal immune tolerance during midterm pregnancy.
维持“半异体”胎儿在母体子宫内生长的免疫耐受机制尚不清楚。CD4+CD25+调节性 T(Treg)细胞被认为参与了母体-胎儿免疫耐受的维持。此外,17β-雌二醇(E2)能够在早孕期间通过 CD4+CD25+Treg 细胞引发免疫抑制。然而,在中期妊娠期间,孕激素(P4)与免疫耐受之间的关系知之甚少,中期妊娠是一个重要时期,其特征是血清中 P4 水平较高而 E2 水平较低。在这里,我们研究了 P4 对中期妊娠期间系统性和局部子宫 CD4+CD25+Treg 细胞扩增和功能的影响。使用体内和体外模型,我们首次提供了证据表明,P4 不仅增加了 CD4+CD25+Treg 细胞的比例和 IL-10 的表达,而且增强了它们的抑制功能。此外,在与中期妊娠相关的生理剂量下,P4 而不是 E2 将 CD4+CD25- T 细胞转化为 CD4+CD25+Treg 细胞。这种转化在体外被核 P4 受体拮抗剂 RU 486 抑制,在 P4 处理的卵巢切除和假孕小鼠模型中体内也被抑制,表明 P4 通过核 P4 受体扩张 Treg 群体。此外,RU 486 显著减少了诱导性流产前胎儿-母体界面 Treg 细胞的数量和功能。有趣的是,随着 Foxp3 的减少,促炎因子增加。总之,这些结果表明 P4 是系统性和局部 CD4+CD25+Treg 细胞的重要调节剂,参与维持中期妊娠期间的母体-胎儿免疫耐受。