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：在过去五年中，全球五岁以下儿童的首要死因已 2016 年，几乎所有婴儿的 10% 都是早产 (PTB)（妊娠 <37 周）引起的并发症。 在美国出生的婴儿早产，据报道，到 2018 年，美国已有 发达国家分娩期间最严重的不良后果估计总共花费 140 亿美元。 从历史上看，PTB 的研究一直具有挑战性，因为人们对其根本原因知之甚少， 并且缺乏生理相关的动物模型，以了解 PTB 的驱动因素。 由于用于研究目的的人体组织（如早产儿标本）的获取受到限制，进一步陷入停滞 分娩通常需要进行病理评估，尽管其机制难以捉摸，但胎盘是一个理想的目标。 发现 PTB 的触发因素，因为在许多情况下都观察到胎盘病变。 虽然炎症在健康足月和早产期间都会升高， 文献强烈表明不同的炎症途径在早产中活跃，并且 与足月出生相比，炎症总体上可能会增加。 记录胎盘绒毛 (PV) 内的免疫细胞对非羊膜内炎症的贡献 人类灵长类动物，并特别发现 PV T 细胞在该模型中具有活性和炎症性。 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 健康妊娠中的PV，当受到来自PV的抗原刺激时可以引发炎症反应 此外，我们小组的初步转录数据显示，T 细胞来自子宫环境。 早产儿 PV 比足月儿 PV 转录更多的激活标记，并且相关的早产儿 PV 具有 因此，我们寻找的结果失败了。 限制抗原呈递至 PV T 细胞会导致 PV T 细胞过度激活、细胞因子增加 生产，以及随后导致 PTB 的胎盘结构破坏。 多组学分析结合早产儿和足月胎盘的体外功能测定，以揭示独特的 PV T 细胞：群体、功能能力、转录机制和滋养层下游反应 我们建议：(1) 对早产和早产的 PV T 细胞进行比较功能分析。 足月妊娠，包括目标 1 中的解剖定位、激活状态和 TCR 谱图。 (2) 在 Aim 中评估 PV T 细胞激活对胎盘滋养层健康和功能的影响 2. 我们的冷冻 PV 样本库和不断收集的新样本、胎盘专业知识 生物学和粘膜免疫学以及多学科科学家团队使我们处于独特的地位 完成这些目标后，这项研究将加深我们对 T 细胞功能的了解。 怀孕和其他免疫耐受情况。