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 phd。