Impact of early microbial exposure on immune ontogeny

项目摘要/摘要 有证据表明，在发育的关键阶段接触微生物可以产生长期的影响。 关于一个人的健康状况。然而，目前还没有概念框架来解释如何 母体接触微生物会影响胎儿和成人的免疫系统。为了填补这一知识空白，我们有 建立了一种新的宠物店小鼠模型，并比较了出生后小鼠CD8+T细胞的个体发育 来自“干净”(防晒系数)或“脏”(宠物店)的妈妈。有趣的是，在肮脏的环境中长大的老鼠 建立了更强大的CD8+T细胞反应，并对感染具有高度抵抗力。为了理解如何 在肮脏的小鼠中，CD8+T细胞的个体发育发生了变化，我们使用了命运映射的时间戳小鼠 研究发现，快速作用的胎儿来源的CD8+T细胞比例较高，而慢作用的成人来源的CD8+细胞比例较少 脏鼠体内存在T细胞。我们还发现，免疫易感性可以在干净的 并通过耗尽胎儿层的CD8+T细胞来污染小鼠。这些数据表明，产妇接触微生物 导致胎儿来源的CD8+T细胞的积累，以保护宿主免受细胞内病原体的侵害。 然而，潜在的机制仍然不清楚。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改变后代的发育分层 T细胞受体。在第一个目标中，我们将把命运映射方法与数学建模相结合，以 了解母亲接触微生物如何导致胎儿来源的CD8+T细胞积累。在 第二个目标，我们将使用配对的单细胞TCR/RNAseq来了解母体微生物环境 改变TCR曲目和免疫防御。从这些研究中获得的知识有望为 新的概念模型用于理解母体在早期的微生物定植如何永久地 对后代的免疫系统和终生疾病风险进行规划。

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.