Immune interactions with commensal microbes in early life

项目总结/摘要 生命早期的事件，特别是那些改变肠道微生物群和免疫发育的事件， 在确定免疫相关疾病的未来风险方面发挥重要作用。例如，据报道， 免疫系统如何遇到物质，喂养方式的时机，卫生和使用 在生命早期使用抗生素，可以改变生命后期免疫驱动疾病的风险。一个共同的主题， 许多研究表明，这些风险因素可能会影响发育中的微生物群。然而，生物 关于生命早期微生物变化如何影响生命后期免疫疾病风险的基础是不完全的 明白我们实验室以前的数据表明，在断奶前， 肠道细菌被选择性地递送到免疫系统， 结肠固有层或远处淋巴组织中局部的免疫群体建立了持久的（寿命， 长）和平衡的免疫系统。在初步研究中，我们观察到大量的差异， 细菌易位，这是证实了抗原特异性T细胞的研究， 对易位细菌的反应因此，我们假设， 在断奶前阶段，对这些移位细菌的免疫应答是随机事件 在正常的个体发育过程中，这是决定个体是否建立 平衡的免疫系统，并防止免疫介导的病理在以后的生活。然而， 这些易位细菌和对这些细菌的抗原特异性应答进行定量的方法仍然是 我们知识的差距。我们将通过识别和描述易位是如何发生的来解决这个问题。 细菌被免疫系统遇到（目的1），并产生试剂来追踪细菌抗原 通过体内T细胞应答进行呈递（目的2）。我们会用这些试剂来整合免疫反应 在断奶前的时期内转移细菌的种类。并将其与 肠道免疫挑战，包括感染和以后的实验性结肠炎（目标3）。如果成功，这 项目可能揭示断奶前易位是一个重要的随机发育变量， 产生肠道免疫健康和体内平衡。

Project Summary/Abstract Events in early life, particularly those altering the gut microbiota and immune development, can have an important role in determining future risk of immune related disorders. For example, it has been reported that the how substances are encountered by the immune system, the timing of feeding practices, hygiene, and the use of antibiotics, in early life can modify the risk of immune driven disorders later in life. A common theme amongst many of these studies is that these risk factors likely affect the developing microbiota. However, the biologic basis for how early life microbial changes can affect the risk of immune disorders later in life is incompletely understood. Previous data from our laboratories have suggested that during this preweaning period, specific live gut bacteria are selectively delivered to the immune system and that interaction of these live bacteria with cellular immune populations locally in the colonic lamina propria or in distant lymphoid tissues establishes a durable (life- long) and balanced immune system. In preliminary studies, we observed substantial variance in the amount of bacterial translocation in this preweaning period, which was corroborated with studies of antigen-specific T cell responses to a translocating bacterial spp. We therefore hypothesize that the magnitude and quality of the immune response to these translocating bacteria species during the preweaning period is a stochastic event during normal ontogeny which represents an important variable in determining whether an individual establishes a balanced immune system and prevents immune mediated pathologies in later life. However, the nature of these translocating bacteria and methods to quantify the antigen-specific responses to these bacteria remain a gap in our knowledge. We will address this question by identifying and characterizing how the translocating bacteria are encountered by the immune system (Aim 1) and generate reagents to track bacterial antigen presentation via T cell responses in vivo (Aim 2). We will use these reagents to integrate the immune response over the preweaning period to translocating bacterial spp. during physiologic development and correlate it with intestinal immune challenges including infection and experimental colitis in later life (Aim 3). If successful, this project may reveal that preweaning translocation is an important stochastic developmental variable involved in generating intestinal immune health and homeostasis.