Maternal Central Immune Tolerance in Reproduction

本研究的总体目标是了解孕期母体对胎儿免疫耐受的机制。母体免疫系统和同种异体胎儿之间的亲密关系是一种无与伦比的生理状态，在妊娠开始和持续期间，抗原性独特的组织特异性蛋白被引入母亲的免疫系统。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是一种转录调节因子，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枢耐受。AIRE确保在发育中的T细胞中建立对这种抗原的耐受性。由Aire调控的组织限制性基因包括许多针对胎儿和胎盘的基因，我们发现Aire不仅在怀孕期间在胸腺中上调，而且全球Aire缺乏可使母亲易于失去胎儿。有趣的是，我们的团队和其他人也发现了Aire在卵巢和子宫中的表达，这表明该转录因子在胸腺外具有额外的作用。在这个项目中，我们的目标是确定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。我们将验证这样的总体假设，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并行发挥作用以支持生育。我们提出了两个具体的目标：目的1.确定Aire缺陷对母体对胎儿免疫耐受的影响。目的2.明确性激素与AIRE在母体对胎儿中枢耐受中的功能联系。目的3.鉴定Aire在女性生育中的免疫非依赖性功能。这些实验的结果有望为母体对胎儿胎盘单位的耐受机制、女性生育能力以及性激素对其的调节提供非常新颖的见解，极大地促进我们对母体对同种异体胎儿移植的耐受的理解。这一结果将对女性在怀孕、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.