Progesterone Promotes Differentiation of Human Cord Blood Fetal T Cells into T Regulatory Cells but Suppresses Their Differentiation into Th17 Cells

Abstract

Progesterone, a key female sex hormone with pleiotropic functions in maintenance of pregnancy, has profound effects on regulation of immune responses. We report here a novel function of progesterone in regulation of naïve cord blood (CB) fetal T cell differentiation into key regulatory T cell subsets. Progesterone drives allogeneic activation-induced differentiation of CB naive, but not adult peripheral blood (PB), T cells into immune suppressive T regulatory cells (Tregs), many of which express FoxP3. Compared to those induced in the absence of progesterone, the FoxP3+ T cells induced in the presence of progesterone highly expressed memory T cell markers. In this regard, the Treg compartment in progesterone-rich CB is enriched with memory type FoxP3+ T cells. Moreover, CB antigen presenting cells were more efficient in inducing FoxP3+ T cells than their PB counterparts. Another related function of progesterone that we discovered was to suppress the differentiation of CB CD4+ T cells into inflammation-associated Th17 cells. Progesterone enhanced activation of STAT5 in response to IL-2 while it decreased STAT3 activation in response to IL-6, which is in line with the selective activity of progesterone in generation of Tregs versus Th17 cells. Additionally, progesterone has a suppressive function on the expression of the IL-6 receptor by T cells. The results identified a novel role of progesterone in regulation of fetal T cell differentiation for promotion of immune tolerance.

Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy

“…Depletion of Tregs results in fetal loss (23). Pregnancy-related hormonal signals, including estrogens and progesterone (1,24,25), appear to support Treg proportion and function, although their exact mode of action remains incompletely understood.…”

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).…”

A Functional Relay from Progesterone to Vitamin D in the Immune System

“…A major mechanism to suppress the T-cell response during pregnancy is mediated by P4. P4 effectively suppresses the generation of T cells producing IFNg (Th1 cells) or IL-17 (Th17 cells) (Piccinni et al, 1995;Miyaura and Iwata, 2002;Lee et al, 2011Lee et al, , 2012. In females, P4 is produced by the corpus luteum of the ovaries after ovulation and in the placenta during pregnancy.…”

“…T cells are regulated at relatively high P4 concentrations (e.g., greater than a few hundred nanograms per milliliter). This level of P4 can effectively suppress the generation of Th1 and Th17 cells (Lee et al, 2011. At the expense of the effector T cells, P4 induces a subset of T cells called ''regulatory T cells.''…”