Progesterone promotes maternal–fetal tolerance by reducing human maternal T‐cell polyfunctionality and inducing a specific cytokine profile

Abstract

Progesterone is a steroid hormone essential for the maintenance of human pregnancy, and its actions are thought to include promoting maternal immune tolerance of the semiallogenic fetus. We report that exposure of maternal T cells to progesterone at physiological doses induced a unique skewing of the cytokine production profile of CD4+ and CD8+ T cells, with reductions not only in potentially deleterious IFN‐γ and TNF‐α production but also in IL‐10 and IL‐5. Conversely, production of IL‐4 was increased. Maternal T cells also became less polyfunctional, focussing cytokine production toward profiles including IL‐4. This was accompanied by reduced T‐cell proliferation. Using fetal and viral antigen‐specific CD8+ T‐cell clones, we confirmed that this as a direct, nonantigen‐specific effect. Yet human T cells lacked conventional nuclear progesterone receptors, implicating a membrane progesterone receptor. CD4+ and CD8+ T cells responded to progesterone in a dose‐dependent manner, with subtle effects at concentrations comparable to those in maternal blood, but profound effects at concentrations similar to those at the maternal–fetal interface. This characterization of how progesterone modulates T‐cell function is important in understanding the normal biology of pregnancy and informing the rational use of progesterone therapy in pregnancies at risk of fetal loss.

Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk

“…Our data suggest that inflammation and microglia/macrophage activity are chronically suppressed in the brain of multiparous mice, consistent with the systemic immune suppression induced by pregnancy seen by others (14). Although parous and nonparous mice had similar estrogen levels, protection could still be mediated by other sex hormones that are increased at the time of pregnancy such as progesterone and human chorionic gonadotropin (hCG) (15,16). A growing literature now supports a prominent role for fetal-derived hCG in promoting immune tolerance during pregnancy and transplantation (17).…”

Influence of oxygen concentration on T cell proliferation and susceptibility to apoptosis in healthy men and women

“…This may partly cause conflicting data in the literature, since some authors demonstrate that lymphocytes proliferate more efficiently at atmospheric oxygen levels [21], while others show that proliferation capacity of lymphocytes is higher at low concentrations of oxygen [22,24]. One of the reasons for the conflicting results could be conducting studies in heterogeneous groups in terms of sex, even if it has long been known that gender can have a significant effect on the activation of lymphocytes [6][7][8][9][10][11]. For this reason we decided to consider both factors together.…”

“…However, the effect of estrogens on immune cells is dose-dependent -low doses of estrogens promote enhanced T H 1 responses and increase cell-mediated immunity [8], while high doses enhance T H 2 responses [9]. Meanwhile, progesterone suppresses production of tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-g) [10], and stimulates regulatory T cell (T REG ) differentiation [11]. Different action of sex steroids is associated with the activation of various signaling pathways in a cell [12].…”

Forbearance of the Immune System during pregnancy: Fetal parasite takes an estrogenic way!

“…Glycodelin A and Progesterone-induced blocking factor (PIBF) are the key mediators of immune regulatory function of P4 [12,13]. Also, progesterone helps in twisting the cytokine generation profile of CD4 + and CD8 + T cells by reducing potentially lethal IFN-U, TNF-α, IL-10 and IL-5 creating a more "tolerogenic" one with IL-4 secretion [14]. Human chorionic gonadotropin, the nature's own immunosuppressant promotes fetal tolerance directly through Tregs, uterine NK cells and indirectly through dendritic cells [15,16].…”