Function of T cells at the Maternal-Fetal Interface

母胎界面 T 细胞的功能

• 批准号: 10452256
• 负责人: Liza Konnikova
• 金额: $ 68.9万
• 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/10452256
• 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 surface; Cells; Child; Childbirth; Chorionic villi; Clone Cells; Coculture Techniques; Collection; Coupled; Cryopreservation; Culture Techniques; 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; Lead; Lesion; Literature; Location; Maternal-Fetal Exchange; Measures; Mediating; Mediator of activation protein; 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.

项目摘要：在过去的五年中，全世界的五岁以下儿童的死亡主要原因 是早产（PTB）的并发症（妊娠37周）。在2016年，几乎所有婴儿中几乎有百分之十 出生于美国的 发达国家分娩期间的大多数不良结果。总体而言，PTB估计成本为140亿 每年美元。从历史上看，PTB受到挑战，因为理解的基本原因， 而且缺乏与身体相关的动物模型。了解PTB的驱动因素的进展 由于早产的标本，由于有限的人体组织的访问而进一步停滞了 交付通常需要病理评估。虽然机制有弹性，但plapeta是理想的目标 对于在许多情况下，观察到PTB的触发因素作为位置病理。这样一种病理是 存在炎症病变。虽然在健康期限和早产期间炎症升高，但 文献强烈表明，差异炎症途径在早产中活跃，并且 与期限出生相比，炎症总体上可能会增加。我们最近发表的作品是第一个 记录斑点绒毛（PV）内免疫细胞对非羊水注射的贡献 人类原发性，特别是发现PV T细胞在该模型中具有活性和炎症性。在 与这些发现一致，我们的初步数据表明，具有内存表型的T细胞存在 健康怀孕中的PV，当用抗原刺激抗原时，可以引起炎症反应 子宫环境。此外，我们组的初步转录数据表明，T细胞来自 早产PV转录比术语PV对应物更多的激活标记和正确的早产PV 滋养细胞细胞凋亡表明的胎盘破坏更大。因此，我们假设失败了 对PV T细胞的抗原表现的限制导致PV T细胞过度活化，细胞因子增加 生产以及随后破坏了斑点结构，导致PTB。该建议将使用 多矩分析以及在早产和术语plecetas上的体外功能测定，以发现独特的PV T细胞：人群，功能能力，转录机械以及滋养细胞的下游响应 在早产。我们建议：（1）在早产和 术语妊娠，包括AIM 1中的解剖学定位，激活状态和TCR曲目概况。 （2）评估PV T细胞激活对AIM的滋养细胞健康和功能的后果 2。我们冷冻保存的PV样品和持续收集的新标本的存储库，专业知识 生物学和粘膜免疫学，以及一个多学科的科学家团队，使我们独特地定位 实现这些目标。完成后，这项研究将增加我们对T细胞功能的理解 怀孕和其他免疫耐受性环境。