Maternal Microbial Influences on Early-life Thymic T cell development

PI/PD：Jain，Nitya博士 项目总结 哺乳动物的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 妊娠9-10周的胎儿胸腺开始播种，“单一阳性”的T细胞开始出现和填充 淋巴器官按GSW15计算。多种其他免疫细胞谱系，包括先天和先天的gdT细胞， 不变自然杀伤T细胞、粘膜相关不变T细胞和先天淋巴样细胞 (ILCs)也存在于胸腺中，并在一个复杂的过程中发育，这是一个受时间调节的复杂过程。在出生时， 仍在发育中的新生儿免疫系统暴露于多种环境抗原，包括 方兴未艾的肠道微生物群。在出生后的头几天和几周内，微生物的定植 对免疫系统发育有深远影响。然而，最近的研究强调了 孕期母体微生物在引导子代肠道免疫细胞动态平衡中的作用是否 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体如何影响早期免疫系统 发展和功能。这项提案具体目标是确定和描述产妇 微生物对子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信号指导着胚胎的发育和功能成熟 子代胸腺表达PLZF的免疫细胞。我们将在实验中验证这一假设 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：分析母体表达的TLR2对子代胸腺淋巴细胞的作用 发展。我们的研究将为早期生命免疫发育过程提供更深入的见解 揭示针对母体微生物的新战略，以促进胎儿和婴儿健康。这些研究还将 在妊娠相关感染的背景下增进我们对母婴沟通的理解 以及它们对后代免疫健康的影响。

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.