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.

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.

We found that progesterone and the synthetic glucocorticoid dexamethasone induce T‐cell death. CD4⁺ regulatory T (T_reg) cells were refractory toward progesterone‐induced cell death, in contrast to conventional CD4⁺ T cells, which resulted in a preferential enrichment of CD4⁺ T_regcells 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.

Our 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.