The overall goal of this research is to understand the mechanisms of maternal immune tolerance to the fetus in pregnancy. The intimacy between the maternal immune system and the fetal allograft is an unparalleled physiological situation in which antigenically unique, tissue-specific proteins are introduced to the mother’s immune system at the commencement and for the duration of pregnancy. When this tolerance fails, infertility, preterm birth and delivery, preeclampsia, or fetal growth restriction may result. Aire is a transcriptional regulator that induces expression of tissue-restricted genes in the thymus, wherein central tolerance to many self-antigens is acquired. Aire ensures that tolerance to such antigens is established in developing T cells. Tissue-restricted genes regulated by Aire include many that are specific to the fetus and placenta, and we have found not only that Aire is upregulated in the thymus during pregnancy, but also that global Aire deficiency can predispose dams to fetal loss. Intriguingly, our group and others have also identified Aire expression in the ovary and uterus, suggesting an additional, extrathymic role of this transcription factor. In this project, we aim to define the role of Aire in immune tolerance to the fetus, elucidate its regulation by sex hormones, and clarify its immune- independent role in reproduction. We will test the overall hypothesis that Aire is required for central immune tolerance the fetus, and that it functions in parallel within the uterus and ovary to support fertility. We propose two specific aims: Aim 1. Determine the impact of Aire deficiency on maternal immune tolerance to the fetus. Aim 2. Ascertain the functional connection between sex hormones and Aire in maternal central tolerance to the fetus. Aim 3. Identify the immune-independent function of Aire in female fertility. The results of these experiments are expected to provide highly novel insight into as-yet unexplored mechanisms of maternal tolerance to the fetal-placental unit, female fertility, and the regulation thereof by sex hormones, greatly advancing our understanding of maternal tolerance to the fetal allograft. The results will have far-reaching implications for women’s wellbeing in the fields of pregnancy, reproductive health, autoimmune disease, transplantation, and cancer immunology.