Impact of early microbial exposure on immune ontogeny

项目总结/摘要 有证据表明，在发育的关键阶段暴露于微生物会产生长期影响 一个人的健康状况。然而，目前还没有概念框架来解释如何 母体微生物暴露塑造了胎儿和成人的免疫系统。为了填补这一知识空白，我们 开发了一种新的宠物店小鼠模型，并比较了出生后小鼠中CD 8 + T细胞的个体发育 从“干净”（SPF）或“肮脏”（宠物店）的母亲。有趣的是，在肮脏的环境中长大的老鼠 具有更强的CD 8 + T细胞应答，并且对感染具有高度抗性。理解如何 在脏小鼠中，CD 8 + T细胞区室的个体发生改变，我们使用命运映射“时间戳”小鼠 发现胎儿来源的快速作用的CD 8 + T细胞比例较高，而成人来源的缓慢作用的CD 8 + T细胞比例较低。 脏老鼠体内的T细胞。我们还发现，免疫易感性可以在清洁的 和脏小鼠通过耗尽胎儿层的CD 8 + T细胞。这些数据表明，母体微生物暴露 导致胎儿来源的CD 8 + T细胞的积累，保护宿主免受细胞内病原体的侵害。 然而，其基本机制仍不明确。我们的假设是母体接触微生物 通过改变细胞存活和外周选择的动态来改变后代的发育分层 T细胞受体。在第一个目标中，我们将联合收割机结合我们的命运映射方法和数学建模， 了解母体微生物暴露如何导致胎儿来源的CD 8 + T细胞的积累。在 第二个目标是，我们将使用配对的单细胞TCR/RNAseq来了解母体微生物环境如何影响胎儿的发育。 改变TCR库和免疫防御。从这些研究中获得的知识预计将提供一个 一种新的概念模型，用于了解早期生命中的母体微生物定植如何永久地 规划后代的免疫系统和终身疾病的风险。

Project Summary / Abstract Evidence has shown that microbial exposure during critical stages of development can have long-lasting effects on the health status of an individual. However, there is currently no conceptual framework to explain how maternal microbial exposure shapes the fetal and adult immune systems. To fill this knowledge gap, we have developed a novel pet-shop mouse model and compared the ontogeny of CD8+ T cells in mice that were born from either ‘clean’ (SPF) or ‘dirty’ (pet-shop) mothers. Interestingly, the mice raised in the dirty environment mounted a more robust CD8+ T cell response and were highly resistant to infection. To understand how the ontogeny of the CD8+ T cell compartment was altered in the dirty mice, we used fate-mapping ‘timestamp’ mice and found a higher proportion of fast-acting fetal derived CD8+ T cells and fewer slow-acting adult derived CD8+ T cells present in the dirty mice. We also found that immune susceptibility could be normalized between clean and dirty mice by depleting the fetal layer of CD8+ T cells. These data indicate that maternal microbial exposure leads to an accumulation of fetal-derived CD8+ T cells that protects the host against intracellular pathogens. However, the underlying mechanisms remain undefined. Our hypothesis is that maternal microbial exposure alters developmental layering in the offspring by changing the dynamics of cell survival and peripheral selection of T cell receptors. In the first aim, we will combine our fate mapping approach with mathematical modeling to understand how maternal microbial exposure leads to an accumulation of fetal-derived CD8+ T cells. In the second aim, we will use paired single cell TCR/RNAseq to understand how the maternal microbial environments alters the TCR repertoire and immune defense. Knowledge gained from these studies is expected to provide a new conceptual model for understanding how maternal microbial colonization in early life can permanently program the offspring’s immune system and life-long disease risk.