Elucidation of mechanisms whereby maternal immune tolerance to the semi-allogeneic fetus is established will yield important insight for development of novel preventative and therapeutic strategies to ensure healthy pregnancies. During pregnancy, progesterone has dramatic effects on the maternal thymus, the location wherein all T cells develop. Using a newly developed murine model, we have found that progesterone action in the thymus is required for optimal pregnancy outcome. Further, we found that the thymus responds early in pregnancy, during the time at which maternal tolerance to the fetus is established. Since the thymus is critical for generating regulatory T cells, which are key for successful pregnancy, our data lead us to hypothesize that pregnancy induces early changes to promote generation of thymus-derived regulatory T cells that in turn confer maternal-fetal tolerance. To address this postulate, we use our novel in vivo model to test the role of progesterone and pregnancy on thymic function and maternal-fetal tolerance in two Specific Aims: AIM 1. Determine the effects of pregnancy and PR in thymic epithelial cells on the dynamics of regulatory T cell production by the thymus. AIM 2. Determine the role of PR in thymic epithelial cells on fetal survival in allogeneic pregnancies and on functionality of TReg in pregnancy. The studies proposed here will overcome our limited understanding of a long-documented, but poorly understood phenomenon in pregnancy. Further, elucidation of the mechanisms of maternal-fetal tolerance, including the role of steroid hormones, have implications extending well beyond pregnancy, and will help to lay foundations for new ways to target and kill cancer cells, improve transplantation outcome, bolster the aging immune system, and prevent autoimmune disease.