Regulation of uterine immune function by progesterone—lessons from the sheep

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Survival of the fetal allograft results from orchestrated adjustments in activity of maternal lymphoid cells as well as in trophoblast gene expression. One molecule that regulates uterine immune responsiveness is progesterone. In fact, uterine skin graft survival and susceptibility to bacterial infections are increased by progesterone. This review focuses on the role of progesterone in regulation of uterine immune function in the sheep. While the importance of progesterone as a regulator of immune function likely varies between species, concepts derived from the sheep model may prove pertinent to other species also. The actions of progesterone on uterine immune function in the ewe change during pregnancy. Before day 50 of gestation, i.e. when the uterus is still dependent upon the corpus luteum as a source of progesterone, concentrations of progesterone are probably not high enough at the maternal–fetal interface to inhibit lymphocyte activation. During this early period of pregnancy, progesterone inhibits uterine immune function by inducing endometrial secretion of a protein called uterine milk protein (UTMP) that itself is inhibitory to lymphocyte function. After day 50 of pregnancy, it is likely that the placenta produces sufficient amounts of progesterone to directly inhibit lymphocyte proliferation. Additional inhibition is achieved because of sustained synthesis of UTMP. Accordingly, progesterone acts to regulate uterine immune function in ways that allows for inhibition of immune responses at the utero–placental interface without systemic immunosuppression.