Function of T cells at the Maternal-Fetal Interface

母胎界面 T 细胞的功能

• 批准号: 10555292
• 负责人: Liza Konnikova
• 金额: $ 67.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-25 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555292
• 关键词: 37 weeks gestation; Abnormal Cell; Activities of Daily Living; Agreement; Anatomy; Animal Model; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptosis; Applications Grants; Architecture; Bioinformatics; Biological Assay; Biology; Cause of Death; Cell Proliferation; Cell Separation; Cell secretion; Cell surface; Cells; Child; Childbirth; Chorionic villi; Clone Cells; Coculture Techniques; Collection; Coupled; Cryopreservation; Cytometry; Data; Development; Environment; Evaluation; Exposure to; Gene Expression Profile; Genetic Transcription; Goals; HLA-DR Antigens; Health; Homeostasis; Human; Immune; Immune Tolerance; Immunology; Immunophenotyping; In Vitro; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Lesion; Literature; Location; Maternal-Fetal Exchange; Measures; Mediating; Mediator; Memory; Modeling; Mucous Membrane; Organoids; Pathologic; Pathology; Pathway interactions; Phenotype; Physiological; Placenta; Placental Biology; Population; Positioning Attribute; Pregnancy; Premature Birth; Premature Labor; Process; Production; Publishing; Reporting; Research; Role; Sampling; Scientist; Specimen; T memory cell; T-Cell Activation; T-Lymphocyte; T-cell receptor repertoire; Techniques; Term Birth; Tissues; United States; Uterus; Work; adaptive immunity; adverse outcome; biobank; comparative; cost; cytokine; experimental study; healthy pregnancy; human data; human tissue; improved; insight; interest; multidisciplinary; multiple omics; nonhuman primate; novel; prevent; rational design; repository; response; targeted treatment; trophoblast

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.

项目概述：在过去五年中，全球五岁以下儿童死亡的主要原因是 早产(PTB)并发症(妊娠37周)。2016年，几乎10%的婴儿 出生在美国的婴儿是早产的，据报道，到2018年，美国有 发达国家在分娩过程中最不利的后果。PTB估计总共耗资140亿美元 每年1美元。从历史上看，肺结核的研究一直具有挑战性，因为人们对其根本原因知之甚少。 而且缺乏与生理相关的动物模型。在理解肺结核的驱动因素方面取得了进展 由于用于研究目的的人体组织有限，进一步停滞不前，例如早产的标本 分娩通常需要病理评估。尽管胎盘在机制上难以捉摸，但它是一个理想的靶子 为了揭示PTB作为胎盘的触发因素，在许多情况下观察到了病理。一种这样的病理是 有炎症性病变。虽然炎症在健康的足月和早产期间都会增加， 文献有力地表明，不同的炎症途径在早产中是活跃的，并且 与足月分娩相比，炎症总体上可能会增加。我们最近出版的作品是第一个 记录胎盘绒毛(PV)内的免疫细胞在非妊娠期羊膜内炎中的作用 并特别发现在这个模型中PV T细胞是活跃的和炎性的。在……里面 与这些发现一致，我们的初步数据显示，具有记忆表型的T细胞存在于 在健康妊娠中的PV，并且当被来自于 子宫环境。此外，我们小组的初步转录数据显示，来自 早产儿PV转录的激活标志物比足月PV对应者和相关的早产儿PV更多 滋养层细胞的凋亡表明胎盘破坏更大。因此，我们假设失败了 限制PV T细胞的抗原提呈导致PV T细胞过度激活，细胞因子增加 产生，以及随后胎盘结构的破坏导致肺结核。这项提案将使用 对早产和足月胎盘进行多组学分析和体外功能分析以揭示独特的PV T细胞：滋养层细胞的种群、功能、转录机制和下游反应 在早产中。我们建议：(1)对早产儿和早产儿的PV T细胞进行功能比较分析 足月妊娠，包括目标1中的解剖定位、激活状态和TCR曲谱。 (2)评估PV T细胞激活对胎盘滋养层细胞健康和功能的影响 2.我们的冷冻PV样本储存库和正在收集的新样本，胎盘专业知识 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 完成这些目标。这项研究完成后，将增加我们对T细胞在糖尿病中的功能的理解 在怀孕和其他免疫耐受环境中。