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

项目概要/摘要 一个人在子宫内和生命早期所经历的微生物暴露量， 影响他们以后的免疫状态。越来越多的报告将接触各种 一系列对不相关病原体具有增强免疫反应的微生物。然而，机制 其中微生物环境塑造免疫系统的发育是未知的。提供 为了深入了解这个问题，我们修改了“宠物商店”小鼠模型，使实验室小鼠暴露于 病原体的整个发展过程。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，这与CD 8 + T细胞的变化有关。 细胞室为了了解CD 8 + T细胞区室在“脏”环境中是如何改变的，我们 使用我们的“时间戳”小鼠，追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加与更高比例的“速效”胎儿来源的 CD 8 + T细胞和较低比例的“慢作用”成人来源的CD 8 + 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细胞区室的发育分层。本提案的主要目标是确定关键 在脏小鼠中改变CD 8 + T细胞发育分层的机制。在目标1中，我将确定如何 脏小鼠中CD 8 + T细胞的产生和维持发生改变。在目标2中，我将评估细胞内在 和环境因素导致脏小鼠中CD 8 + T细胞组成的改变。这项建议旨在 创建一个概念框架，以了解早期生活中的微生物暴露如何改变 CD 8 + T细胞区室。从这一建议中获得的知识有可能产生一种范例 改变了我们对免疫个体发生和免疫细胞指令的理解。

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.