Impact of microbial exposure on immune development

项目摘要/摘要 在子宫和出生后接触微生物会永久性地影响一个人的免疫系统和生命-- 长期的疾病风险。然而，微生物暴露与免疫个体发育之间的关系仍然很差。 已定义。我们已经开发了一个小鼠模型，以更好地了解母体微生物环境如何 塑造后代的免疫系统。我们的初步数据表明，接触微生物的时间已经 对晚年细胞内病原体的易感性产生了深远的影响。因此，这项提案的一个主要目标是 就是剖析母亲接触微生物如何改变子代CD8+T细胞的发育和功能 细胞。为了实现这一目标，我们将使用一些尖端方法来检验以下假设 微生物暴露通过改变CD8+T细胞的发育层来编程免疫易感性 对感染的反应。首先，Aim我们将确定微生物暴露如何改变CD8+T细胞的方式 牢房隔间是“拼装的”。从这个目标的结果将提供洞察如何组成和 后代中CD8+T细胞的编程与生命早期的微生物接触有关。在 第二个目标，我们将研究微生物暴露的数量和时间如何改变后代对 细胞内的病原体。我们特别感兴趣的是确定在特定的时间内微生物暴露如何 发育窗口期(在子宫内、出生后)会改变后代对感染的CD8+T细胞反应 生活。我们的建议旨在提供一个新的概念框架，以了解微生物在 早年的生命会导致后代的免疫系统发生终生的、可能不可逆转的变化。获得的知识 这些研究有望拓宽我们对免疫发育和细胞的基本了解。 中介免疫。

Project Summary / Abstract The exposure to microbes in utero and after birth permanently programs an individual’s immune system and life- long disease risk. However, the relationship between microbial exposure and immune ontogeny remain poorly defined. We have developed a mouse model to better understand how the maternal microbial environment shapes the offspring’s immune system. Our preliminary data indicates that the timing of microbial exposure has a profound impact on susceptibility to intracellular pathogens later in life. Thus, a main objective of this proposal is to dissect out how maternal microbial exposure alters the development and function of the offspring’s CD8+ T cells. To accomplish this objective, we will use a number of cutting-edge approaches to test the hypothesis that microbial exposure programs immune susceptibility by altering the developmental layers of the CD8+ T cell response to infection. In the first, aim we will determine how microbial exposure changes the way the CD8+ T cell compartment is ‘put-together.’ Results from this aim will provide insight into how the composition and programming of CD8+ T cells in the offspring are linked to microbial exposure in the earliest days of life. In the second aim, we will examine how the amount and timing of microbial exposure alter the offspring’s response to intracellular pathogens. We are particularly interested in determining how microbial exposure during specific windows of development (in utero, post-natal) changes the offspring’s CD8+ T cell response to infection later in life. Our proposal aims to provide a new conceptual framework for understanding how microbial colonization in early life leads to life-long, potentially irreversible, changes in the offspring’s immune system. Knowledge gained from these studies is expected to broaden our fundamental understanding of immune development and cell- mediated immunity.