Progesterone modulates the T‐cell response via glucocorticoid receptor‐dependent pathways

Abstract

Problem Steroid hormones such as progesterone and glucocorticoids rise during pregnancy and are accountable for the adaptation of the maternal immune system to pregnancy. How steroid hormones induce fetal tolerance is not fully understood. We hypothesized that steroid hormones selectively regulate the T‐cell response by promoting T‐cell death. Method of study We incubated murine spleen cells isolated from non‐pregnant and pregnant mice with physiological concentrations of steroid hormones in vitro and analyzed T‐cell subsets after 48 h of incubation. ResultsWe found that progesterone and the synthetic glucocorticoid dexamethasone induce T‐cell death. CD4+ regulatory T (Treg) cells were refractory toward progesterone‐induced cell death, in contrast to conventional CD4+ T cells, which resulted in a preferential enrichment of CD4+ Tregcells in culture. T cells isolated from pregnant mice at early and late gestation showed comparable sensitivity to steroid‐induced cell death. The target receptor for progesterone in immune cells is controversially discussed. We provide here support of progesterone binding to the glucocorticoid receptor as only T cells lacking the glucocorticoid but not the progesterone receptor showed resistance against progesterone‐induced death. ConclusionsOur results indicate that high levels of progesterone during pregnancy can induce selective T‐cell death by binding the glucocorticoid receptor. Although physiological hormone concentrations were used, due to different bioavailability of steroid hormones in vivo these results have to be validated in an in vivo model. This mechanism might ensure immunological tolerance at the feto‐maternal interface at gestation.

Steroids, Pregnancy and Fetal Development

“…Also targeted gene deletion of the GR on T cells in mice pinpoints that GR and not PR is an upstream promotor of Treg expansion during pregnancy. In vitro approaches further support that GR mediates the expansion of T regulatory cells by selective induction of apoptosis in conventional T cells (9,10). These mechanisms are at play during pregnancy, as in a mouse model of experimental autoimmune encephalomyelitis, GR deletion in T cells prevented pregnancy-induced expansion of T regulatory cells, as well the corresponding mitigation of autoimmunity (9).…”

“…Recent data emerging from mice carrying cell specific gene deletions underscore that pathways downstream the GR in immune cells are critically involved in promoting immune tolerance during pregnancy (9,10). As until recently this tolerance was considered to be primary modulated by signaling through the intracellular PR, these novel observations invite to reexamine aspects of endocrine immune regulation during pregnancy.…”

“…Intriguingly, although progesterone is generally acknowledged to promote maternal immune tolerance to alloantigens derived from the conceptus, progesterone receptors are not ubiquitously expressed on immune cells (9). Light was shed into this enigma only very recently, when it was identified that pivotal features of progesterone induced-maternal immune adaptations to pregnancy are mediated via the glucocorticoid receptor (9,10). Hence, in the present review manuscript, we aim to revisit the current evidence about the synthesis and interplay between glucocorticoids and progesterone during pregnancy, their impact on the immune system and consequences for pregnancy maintenance and fetal development.…”

Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus

“…P4 application is also protective against LPS-induced PTB in mice via prevention of inflammation-induced cervical remodeling, cervical macrophage infiltration, and MMP9 expression that precedes PTB, possibly through the disruption of complement signaling on macrophages [77]. P4 is known as a strong immunomodulator, it induces stable Treg cells, arrests DC in a tolerogenic state, and suppresses inflammatory responses [122][123][124]. P4 signaling withdrawal may therefore be one mechanism of immune modulation leading to PTB.…”

Endothelial Cells in the Decidual Bed Are Potential Therapeutic Targets for Preterm Birth Prevention

“…Non-uterine tissues, such as spleen and liver, do not show specific PR staining ( Figure S3). Using T cell-specific deletion of PR and glucocorticoid receptor (GR), it was shown that P 4 -induced T cell death is mediated by GR but not PR (Hierweger et al, 2019). In a recent study, single-cell analysis of human decidual cells in the first trimester shows that PR expression is very low to undetectable in NK cells, dendritic cells (DCs), monocytes, macrophages, and T cells as opposed to a significant presence of GR expression in these cell types.…”