Maternal Central Immune Tolerance in Reproduction

本研究的总体目标是了解孕妇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状况，在怀孕开始和怀孕期间，抗原独特的组织特异性蛋白质被引入母体免疫系统。当这种耐受性失败时，可能会导致不孕、早产和分娩、先兆子痫或胎儿生长受限。Aire是一种转录调节剂，可诱导胸腺组织限制性基因的表达，从而获得对许多自身抗原的中心耐受性。Aire确保在发育中的T细胞中建立对这些抗原的耐受性。受Aire调控的组织限制性基因包括许多胎儿和胎盘特异性的基因，我们发现不仅在怀孕期间胸腺中Aire被上调，而且全球Aire缺乏可导致胎儿丢失。有趣的是，我们的团队和其他人也在卵巢和子宫中发现了Aire的表达，这表明该转录因子具有额外的胸腺外作用。在本项目中，我们旨在明确Aire在胎儿免疫耐受中的作用，阐明其受性激素的调节，并阐明其在生殖中的免疫独立作用。我们将测试总体假设，即Aire是胎儿中枢免疫耐受所必需的，并且它在子宫和卵巢内平行起作用以支持生育。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。这些实验的结果有望为尚未探索的母体对胎儿-胎盘单元的耐受机制、女性生育能力以及性激素对其的调节提供高度新颖的见解，极大地推进我们对母体对胎儿异体移植耐受的理解。研究结果将对妇女在怀孕、生殖健康、自身免疫性疾病、移植和癌症免疫学等领域的福祉产生深远影响。

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.