Progesterone Increases Systemic and Local Uterine Proportions of CD4+CD25+ Treg Cells during Midterm Pregnancy in Mice
Progesterone Increases Systemic and Local Uterine Proportions of CD4+CD25+ Treg Cells during Midterm Pregnancy in Mice
复制标题
DOI：
10.1210/en.2010-0426
复制
发表时间：
2010-11-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Bin
中科院分区：
文献类型：
--
作者：
Mao, Guanping;Wang, Junpeng;Wang, Bin
通过免疫耐受维持母体子宫内“半外来”胎儿生长的机制尚不清楚。CD 4（+）CD 25（+）调节性T（Treg）细胞参与母胎免疫耐受的维持。此外，17 β-雌二醇（E2）能够在妊娠早期通过CD 4（+）CD 25（+）Treg细胞启动免疫抑制。然而，关于孕激素（P4）和中期妊娠期间免疫耐受之间的关系知之甚少，中期妊娠是一个重要的时期，其特征是血清中P4水平较高，但E2水平较低。在这里，我们研究了P4对中期妊娠小鼠全身和局部子宫CD 4（+）CD 25（+）Treg细胞的扩增和功能的影响。使用体内和体外模型，我们提供了第一个证据表明，P4不仅增加了CD 4（+）CD 25（+）Treg细胞的比例和IL-10的表达，而且还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CD 4（+）CD 25（+）T细胞转化为CD 4（+）CD 25（+）Treg细胞。这种转化在体外被核P4受体拮抗剂RU 486抑制，在体内在P4处理的卵巢切除和假孕小鼠模型中被抑制，表明P4通过核P4受体扩增Treg群体。此外，RU 486在人工流产开始前显著降低了胎儿-母体界面中Treg细胞的数量和功能。有趣的是，随着Foxp 3的减少，促炎因子增加。总之，目前的结果表明，P4是全身和局部CD 4（+）CD 25（+）Treg细胞的重要调节因子，其参与维持中期妊娠期间的母胎免疫耐受。（内分泌学151：5477-5488，2010）
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, 17 beta-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. (Endocrinology 151: 5477-5488, 2010)