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 Ph.D. 项目摘要子宫内相对无菌的胎儿环境中的哺乳动物胎儿发育。在人类中，前体细胞在妊娠周（GSW）9-10播种胎儿胸腺，“单阳性” T细胞开始出现并填充 GSW15的淋巴器官。其他多种免疫细胞系列，包括先天和先天的GD T细胞，不变的天然杀伤T（INKT）细胞，粘膜相关的不变T（MAIT）细胞和先天淋巴样细胞（ILC）也在胸腺中发现，并在暂时调节的复杂过程中发展。出生时，仍在开发新生儿免疫系统，暴露于多种环境抗原肠肠菌群。出生后的头几天和几周，微生物定植对免疫系统开发的深刻影响。但是，最近的研究强调了孕产妇微生物在妊娠期间引导其后代的肠道免疫稳态。无论母体微生物还影响胎儿和产后胸腺免疫细胞发育，功能是不知道。我们的长期目标是了解微生物和微生物介质如何影响早期免疫系统发展和功能。该提案的具体目标是识别和表征孕产妇发展中胸腺细胞的微生物影响。根据我们的初步数据，我们假设母体微生物和母体TLR2信号指导的发展和功能成熟胸腺表达胸腺PLZF的免疫细胞。我们将在实验中检验该假设以下目标。目标1：确定影响后代胸腺淋巴细胞的母体微生物的作用发展。 AIM 2：剖析主要表达TLR2在后代胸腺淋巴细胞上的作用发展。我们的研究将为早期生命免疫发育过程提供更深入的见解揭示针对物物微生物以促进胎儿和婴儿健康的新策略。这些研究也将在与妊娠相关感染的背景下以及它们对后代免疫健康的影响。