The role of early microbial exposure in the ontogeny of CD8+ T cells

项目摘要/摘要 一个人在子宫中和生命早期所经历的微生物暴露的量对一个人来说是持久而深刻的 对他们晚年的免疫状态产生影响。越来越多的报告将接触到不同的 一系列对无关病原体具有增强免疫反应的微生物。然而，这些机制 在其中微生物环境塑造免疫系统的发展是未知的。要提供 为了深入了解这个问题，我们修改了宠物店小鼠模型，使实验室小鼠暴露在 它们整个发育过程中的病原体。有趣的是，我们发现在“肮脏”环境中饲养的老鼠 增强对细胞内感染的免疫保护与CD8+T细胞的变化有关 牢房。为了了解CD8+T细胞是如何在“肮脏”的环境中改变的，我们 使用我们的“时间戳”小鼠，跟踪不同生命阶段产生的T细胞的命运。我们发现 对细胞内病原体的抵抗力增强与更高比例的快速反应的胎儿来源有关 CD8+T细胞和较低比例的“慢作用”成人来源的CD8+T细胞存在于成年期。这些数据 这表明在生命早期接触微生物会通过改变免疫系统中的 外周T细胞室的发育分层。这项提案的主要目标是找出关键 改变脏鼠CD8+T细胞发育分层的机制。在目标1中，我将确定如何 肮脏的小鼠的CD8+T细胞的产生和维持发生了变化。在目标2中，我将评估细胞固有的 环境因素也是导致脏鼠CD8+T细胞组成改变的原因之一。这项提议旨在 创建一个概念框架，以了解早期生命中的微生物暴露如何改变儿童的发育 CD8+T细胞亚群。从这一提议中获得的知识有可能导致一种范例 我们对免疫个体发育和免疫细胞指导的理解发生了转变。

Project Summary/Abstract The amount of microbial exposure an individual experiences in utero and early in life has a lasting and profound impact on their immune status later in life. A growing number of reports have associated exposure to a diverse range of microbes with an enhanced immune response against unrelated pathogens. However, the mechanisms in which the microbial environment shapes the development of the immune system is unknown. To provide insight into this question, we modified the ‘pet-shop’ mouse model so that laboratory mice would be exposed to pathogens for the entirety of their development. Interestingly, we found mice raised in a ‘dirty’ environment have enhanced immune protection against intracellular infections, which was associated with changes in the CD8+ T cell compartment. To understand how the CD8+ T cell compartment was altered in a ‘dirty’ environment, we used our ‘timestamp’ mice and tracked the fates of T cells produced at different stages of life. We found that increased resistance to intracellular pathogens was linked to a higher proportion of ‘fast-acting’ fetal-derived CD8+ T cells and lower proportion of ‘slow-acting’ adult-derived CD8+ T cells present in adulthood. These data suggests that microbial exposure in early life leads to permanent changes in the immune system by altering the developmental layering of the peripheral T cell compartment. The main goal of this proposal is to identify the key mechanisms that alter the developmental layering of CD8+ T cells in dirty mice. In aim 1, I will determine how the production and maintenance of CD8+ T cells is altered in dirty mice. In aim 2, I will assess how cell-intrinsic and environmental factors contribute to the altered composition of CD8+ T cells in dirty mice. This proposal aims to create a conceptual framework to understand how microbial exposure in early life alters the development of the CD8+ T cell compartment. Knowledge gained from this proposal has the potential to result in a paradigm shift of how we understand immune ontogeny and immune cell instruction.