Function of T cells at the Maternal-Fetal Interface

项目摘要：在过去的五年里，全世界五岁以下儿童死亡的主要原因是 早产（PTB）（<37周妊娠）的并发症。2016年，几乎10%的婴儿 据报道，到2018年， 在发达国家，分娩过程中最不利的结果。总的来说，PTB估计耗资140亿美元， 美元每年。从历史上看，PTB一直是具有挑战性的研究，因为根本原因是知之甚少， 并且缺乏生理学相关的动物模型。在了解肺结核的驱动因素方面取得了进展， 由于出于研究目的而限制获取人体组织， 分娩通常需要病理学评估。虽然机制上难以理解，但胎盘是一个理想的靶点 用于发现PTB的触发因素，因为在许多情况下观察到胎盘病变。一种这样的病理是 存在炎性病变。虽然炎症在健康足月和早产期间都会升高， 文献强烈提示，不同的炎症途径在早产中是活跃的， 与足月分娩相比，炎症总体上可能增加。我们最近发表的工作是第一个 记录了胎盘绒毛（PV）内的免疫细胞对非羊膜炎患者羊膜内炎症的贡献。 人类灵长类动物，特别是揭示了PV T细胞在该模型中是活跃的和炎性的。在 与这些发现一致，我们的初步数据表明，具有记忆表型的T细胞存在于 PV在健康妊娠中，并且当用来自 子宫环境此外，来自我们小组的初步转录数据显示， 早产儿肺静脉转录的激活标志物比足月儿肺静脉转录的激活标志物多， 滋养层细胞凋亡表明胎盘破坏更严重。因此，我们假设 抗原呈递至PV T细胞的限制导致PV T细胞过度活化，细胞因子增加， 生产，并随后破坏胎盘结构，导致PTB。该提案将使用 多组学分析结合早产和足月胎盘的体外功能测定，以发现独特的PV T细胞：滋养层细胞的群体、功能、转录机制和下游反应 早产的几率我们建议：（1）对早产儿PV T细胞进行比较功能分析， 足月妊娠，包括Aim 1中的解剖学定位、激活状态和TCR谱。 (2)评估PV T细胞活化对Aim中胎盘滋养层健康和功能的影响 2.我们的冻存PV样本库和正在进行的新标本收集， 生物学和粘膜免疫学，以及多学科的科学家团队使我们处于独特的地位， 实现这些目标。这项研究完成后，将增加我们对T细胞功能的理解， 妊娠和其他免疫耐受环境中。

Project Summary: Over the past five years, the leading cause of death worldwide for children under five has been complications from preterm birth (PTB) (<37 weeks’ gestation). In 2016, almost ten percent of all infants born in the United States were delivered prematurely, and by 2018 the United States was reported to have the most adverse outcomes during childbirth in the developed world. Collectively, PTB is estimated to cost 14 billion dollars annually. Historically, PTB has been challenging to study as the underlying causes are poorly understood, and there is a lack of physiologically relevant animal models. Progress in understanding the drivers of PTB has been further stalled by limited access to human tissue for research purposes, as specimens from preterm deliveries usually require pathological evaluation. Though elusive in mechanism, the placenta is an ideal target for uncovering triggers of PTB as placental pathologies are observed in many cases. One such pathology is the presence of inflammatory lesions. While inflammation is elevated during both healthy term and preterm labor, the literature strongly suggests that differential inflammatory pathways are active in preterm deliveries, and inflammation may overall be increased compared to term births. Our recently published work was the first to document the contribution of immune cells within the placental villi (PV) to intraamniotic inflammation in non- human primates and specifically uncovered that PV T cells are active and inflammatory in this model. In agreement with these findings, our preliminary data show that T cells with memory phenotypes are present in the PV in healthy pregnancy and can elicit inflammatory responses when stimulated with antigens from the uterine environment. Furthermore, preliminary transcriptional data from our group revealed that T cells from preterm PV transcribe more activation markers than term PV counterparts and correlatively preterm PV have greater placental destruction indicated by apoptosis of trophoblast cells. We, therefore, hypothesized that failed restriction of antigen presentation to PV T cells leads to PV T cell overactivation, increased cytokine production, and subsequent destruction of placental architecture resulting in PTB. This proposal will use multi-omic analysis coupled with in vitro functional assays on preterm and term placentas to uncover unique PV T cells: populations, functional capacity, transcriptional machinery, and downstream responses on trophoblasts in preterm birth. We propose: (1) Perform comparative functional analyses of PV T cells in preterm and term pregnancies, including anatomic localization, activation state, and TCR repertoire profiles in Aim 1. (2) Evaluate the consequences of PV T cell activation on placental trophoblast health and function in Aim 2. Our repository of cryopreserved PV samples and ongoing collection of new specimens, expertise in placental biology and mucosal immunology, and a multidisciplinary team of scientists make us uniquely positioned to accomplish these goals. At its completion, this study will increase our understanding of the function of T cells in pregnancy and in other immunological tolerance settings.