Progesterone Increases Systemic and Local Uterine Proportions of CD4+CD25+ Treg Cells during Midterm Pregnancy in Mice

Abstract

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.

Membrane progesterone receptors in human regulatory T cells: a reality in pregnancy

“…5 The withdrawal of hormones at the end of pregnancy may affect FoxP3 expression by Treg cells, which was shown to be enhanced by progesterone in human studies. 3 Other authors postulate that progesterone, whose maximum levels are seen at the end of pregnancy, has the capacity to reduce FoxP3 expression by Treg cells in vitro. 25 Moreover, recent data indicate a significant decrease of Treg cells expressing FoxP3 in the 3rd trimester and women in labour at term.…”

“…2 The abundance or modulation of systemic regulatory T cells (Treg) could be involved in pregnancy complications. 3,4 However, it is not known whether the Treg suppressive mechanism is specific to PTB or if it is also involved in spontaneous normal term birth. 5 Progesterone has a major role in pregnancy maintenance and its secretion has been demonstrated in the amnion, chorion and decidua in humans.…”

Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

“…stasis by inhibiting overshooting reactions in a number of tissues in the body (31)(32)(33). Both progesterone and HMOX-1 can suppress CD4 + effector T cell responses and induce the generation of CD4 + Tregs (34)(35)(36)(37), which also promote maternal immune tolerance to the fetus (38,39). Maternal CD8 + T cell responses can also affect placental function (40)(41)(42).…”

Mechanisms of Maternal Immune Tolerance During Pregnancy

“…In these studies, physiological doses of progesterone were shown to significantly increase the population of Treg cells (Lee et al, 2011;Mao et al, 2010). However, in contrast to these data, Mjosberg et al showed using an in vitro model, that progesterone reduced the Treg cell population in PBMC from nonpregnant women (Mjosberg et al, 2009).…”