Maternal Central Immune Tolerance in Reproduction

本研究的总体目标是了解妊娠期母体对胎儿免疫耐受的机制。母体免疫系统和胎儿同种异体移植物之间的亲密关系是一种无与伦比的生理情况，其中抗原性独特的组织特异性蛋白质在妊娠开始时和妊娠期间被引入母体的免疫系统。当这种耐受失败时，可能导致不孕、早产和分娩、先兆子痫或胎儿生长受限。Aire是诱导胸腺中组织限制性基因表达的转录调节因子，其中获得了对许多自身抗原的中枢耐受性。Aire确保在发育中的T细胞中建立对这些抗原的耐受性。由Aire调控的组织限制性基因包括许多对胎儿和胎盘特异的基因，我们发现不仅Aire在妊娠期间在胸腺中上调，而且整体Aire缺乏可使母体易于流产。有趣的是，我们的研究小组和其他人也发现了卵巢和子宫中的Aire表达，表明这种转录因子的额外的胸腺外作用。在这个项目中，我们的目标是确定在胎儿免疫耐受的作用，阐明其调节性激素，并阐明其在生殖中的免疫独立的作用。我们将测试的总体假设，即Aire是所需的中枢免疫耐受的胎儿，它的功能在子宫和卵巢平行，以支持生育。我们提出两个具体目标：目标1。确定Aire缺乏对母体对胎儿免疫耐受的影响。目标2.确定性激素和Aire在母体对胎儿的中枢耐受中的功能联系。目标3.确定Aire在女性生育中的免疫独立功能。这些实验的结果预计将为尚未探索的母体对胎儿-胎盘单位的耐受性、女性生育能力及其性激素的调节机制提供高度新颖的见解，极大地推进我们对母体对胎儿同种异体移植物耐受性的理解。这些结果将对怀孕、生殖健康、自身免疫性疾病、移植和癌症免疫学领域的妇女健康产生深远的影响。

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.