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Maternal Microbial Influences on Early-life Thymic T cell development

母体微生物对生命早期胸腺 T 细胞发育的影响

基本信息

批准号：
10405567
负责人：
Nitya Jain
金额：
$ 49.12万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-12 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405567
关键词：
Antigens Bacteroides fragilis Biological Response Modifiers Birth Cell Lineage Cells Communication Complex Cytotoxic T-Lymphocytes Data Development Developmental Process Disease susceptibility Doctor of Philosophy Elderly Environment Exposure to Fetal Development Fetal health Goals Homeostasis Human Human Milk Immune Immune system Immunity Immunoglobulin G Impairment Infant Infant Health Infection Intestines Life Ligands Lymphocyte Lymphoid Cell Maternal-Fetal Exchange Mediator of activation protein Microbe Mothers Mucous Membrane Mus Newborn Infant Outcome Pathway interactions Pattern recognition receptor Physiological Play Polysaccharides Pregnancy Process Proxy Regulation Role Seeds Shapes Signal Transduction Sterility Systems Development T-Cell Development T-Lymphocyte TLR2 gene Testing Thymus Gland Time ZNF145 gene base experimental study fetal gut microbiota host microbiota immune health immunoregulation in utero insight lymphoid organ maternal microbiota microbial microbial colonization microbiota neonate offspring postnatal precursor cell primary lymphoid organ sensor transcription factor

项目摘要

PI/PD: Jain, Nitya Ph.D. PROJECT SUMMARY The mammalian fetus develops in a relatively sterile fetal environment in utero. In humans, precursor cells seed the fetal thymus at gestational week (GSW) 9-10 and ‘single-positive’ T cells begin to arise and populate lymphoid organs by GSW15. Multiple other lineages of immune cells including innate and innate-like gd T cells, invariant Natural Killer T (iNKT) cells, Mucosal Associated Invariant T (MAIT) cells and Innate Lymphoid cells (ILCs) are also found in the thymus and develop in a complex process that is temporally regulated. At birth, the still developing immune system of the newborn is exposed to a multitude of environmental antigens including the burgeoning intestinal microbiota. Microbial colonization during the first days and weeks after birth has profound effects on immune system development. However, recent studies have highlighted the contribution of maternal microbes in guiding intestinal immune cell homeostasis in their offspring during gestation. Whether maternal microbes also influence fetal and postnatal thymic immune cell development and function is not known. Our long-term goal is to understand how microbes and microbial mediators impact early-life immune system development and function. The specific objective of this proposal is to identify and characterize maternal microbial influence of developing thymic cells in progeny. Based on our preliminary data, we hypothesize that maternal microbes and maternal TLR2 signals direct the development and functional maturation of thymic PLZF-expressing immune cells in offspring. We will test this hypothesis in the experiments of the following Aims. Aim 1: Determine the role of maternal microbes in influencing offspring thymic lymphocyte development. Aim 2: Dissect the role of maternally expressed TLR2 on offspring thymic lymphocyte development. Our studies will provide deeper insight into an early life immune developmental process that will reveal new strategies to target maternal microbes to promote fetal and infant health. These studies will also advance our understanding of maternal-fetal communications in the context of pregnancy-related infections and their impact on offspring immune health.

PI/PD：Jain、Nitya 博士项目概要哺乳动物胎儿在子宫内相对无菌的胎儿环境中发育。在人类中，前体细胞在妊娠周 (GSW) 9-10 时在胎儿胸腺中播种，“单阳性”T 细胞开始出现并聚集 GSW15 的淋巴器官。多种其他免疫细胞谱系，包括先天性和先天性 gd T 细胞，不变自然杀伤 T (iNKT) 细胞、粘膜相关不变 T (MAIT) 细胞和先天淋巴细胞 (ILC) 也存在于胸腺中，并在受时间调节的复杂过程中发育。出生时，新生儿的免疫系统仍在发育，会暴露于多种环境抗原，包括迅速发展的肠道微生物群。出生后头几天和几周内微生物定植对免疫系统发育产生深远影响。然而，最近的研究强调了母体微生物在妊娠期间指导后代肠道免疫细胞稳态。无论母体微生物也会影响胎儿和出生后胸腺免疫细胞的发育和功能不知道。我们的长期目标是了解微生物和微生物介质如何影响生命早期的免疫系统发育和功能。该提案的具体目标是确定和描述孕产妇的特征微生物对后代胸腺细胞发育的影响。根据我们的初步数据，我们假设母体微生物和母体 TLR2 信号指导发育和功能成熟子代中表达胸腺 PLZF 的免疫细胞。我们将在实验中检验这个假设以下目标。目标 1：确定母体微生物在影响子代胸腺淋巴细胞中的作用发展。目标 2：剖析母体表达的 TLR2 对子代胸腺淋巴细胞的作用发展。我们的研究将提供对生命早期免疫发育过程的更深入的了解，这将揭示针对母体微生物以促进胎儿和婴儿健康的新策略。这些研究也将增进我们对妊娠相关感染背景下母婴沟通的理解及其对后代免疫健康的影响。