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

• 批准号: 10065870
• 负责人: Nitya Jain
• 金额: $ 50.4万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-12 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065870
• 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

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 项目摘要 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， 在妊娠周（GSW）9-10时接种胎儿胸腺，“单阳性”T细胞开始产生并繁殖 GSW 15的淋巴器官。多种其他免疫细胞谱系，包括先天性和先天性样gd T细胞， 不变自然杀伤T（iNKT）细胞、粘液相关不变T（MAIT）细胞和先天性类淋巴细胞 （ILC）也存在于胸腺中，并在时间调节的复杂过程中发育。出生时 新生儿仍在发育的免疫系统暴露于多种环境抗原， 迅速增长的肠道菌群在出生后的最初几天和几周内， 对免疫系统发育的深远影响。然而，最近的研究强调了 母体微生物在指导其后代妊娠期间肠道免疫细胞稳态中的作用。是否 母体微生物也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早期免疫系统 发展和功能。这项建议的具体目标是确定产妇死亡率并确定其特点， 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TLR 2信号指导了哺乳动物的发育和功能成熟。 胸腺PLZF表达免疫细胞的后代。我们将在实验中检验这一假设。 遵循目标。目的1：确定母体微生物对子代胸腺淋巴细胞的影响 发展目的2：探讨母源性TLR 2对子代胸腺淋巴细胞的作用 发展我们的研究将提供更深入的了解生命早期的免疫发育过程， 揭示了针对母体微生物以促进胎儿和婴儿健康的新策略。这些研究还将 促进我们对妊娠相关感染背景下母胎沟通的理解 及其对后代免疫健康的影响。