Nuclear Progesterone Receptor Expressed by the Cortical Thymic Epithelial Cells Dictates Thymus Involution in Murine Pregnancy

Abstract

Progesterone is a gonadal pro-gestational hormone that is absolutely necessary for the success of pregnancy. Most notable actions of progesterone are observed in the female reproductive organs, the uterus and the ovary. Acting through the nuclear progesterone receptor (PGR), progesterone prepares the endometrium for implantation of the embryo. Interestingly, the maternal thymus also is a known expressor of Pgr; its absence is associated with murine pregnancy complications. However, the localization of its expression and its functional importance were not known. Here, we used a transgenic dual fluorescent reporter mouse model and genetic deletion of Pgr in Foxn1+ thymic epithelial cells (TEC) to demonstrate TEC-specific Pgr expression in pregnancy, especially in the cortex where thymocyte maturation occurs. Using our TEC-specific Pgr deletion mouse model, we demonstrate that TEC-specific Pgr is necessary for pregnancy-induced thymic involution in pregnancy. Our investigation reveals that PGR expression is upregulated in the cortical thymic epithelial cells during pregnancy, and that PGR expression is important for thymic involution during murine pregnancy.

Fetal‐placental antigens and the maternal immune system: Reproductive immunology comes of age*

“…145 Further, representation and regulation by AIRE in thymic medullary epithelial cells includes fetus and placenta-specific antigens (Petroff, Grzesiak & Ahn, unpublished). [131][132][133]146 The ovary and placenta are likely primary targets of autoimmunity in women with APS-1, as evidenced by the presence of anti-gonadal and anti-placental antibodies. [147][148][149] Studies using AIRE-deficient mice have also revealed profound female infertility or subfertility.…”

“…In mice, more than 70% of thymic mass and 95% of cellularity disappears by the second half of pregnancy, rebounding only after lactation. 146,159 This may occur in all mammals, including women, which undergo altered thymic output during pregnancy. [160][161][162][163] The nuclear progesterone receptor is dramatically upregulated in cortical thymic epithelial cells and mediates thymic involution, likely by signaling changes in thymocyte trafficking and lymphopoiesis.…”

“…[160][161][162][163] The nuclear progesterone receptor is dramatically upregulated in cortical thymic epithelial cells and mediates thymic involution, likely by signaling changes in thymocyte trafficking and lymphopoiesis. 146,164,165 Further, prevention of thymic involution by cell-specific deletion of progesterone receptor may compromise allogeneic pregnancy, 146,165 suggesting a possible role in tolerance to paternally inherited antigens.…”

“…More than 60% of women suffering from APS‐1 are affected by primary infertility or fetal loss 145 . Further, representation and regulation by AIRE in thymic medullary epithelial cells includes fetus and placenta‐specific antigens (Petroff, Grzesiak & Ahn, unpublished) 131–133,146 . The ovary and placenta are likely primary targets of autoimmunity in women with APS‐1, as evidenced by the presence of anti‐gonadal and anti‐placental antibodies 147–149 .…”

“…Under the influence of progesterone, the thymus involutes dramatically in pregnancy. In mice, more than 70% of thymic mass and 95% of cellularity disappears by the second half of pregnancy, rebounding only after lactation 146,159 . This may occur in all mammals, including women, which undergo altered thymic output during pregnancy 160–163 .…”