Microbiota Specific T Cell Selection

项目摘要 几千年来，人类与大量的微生物共同进化，统称为 微生物区系，它提供许多关键信号，帮助免疫系统的发育和正常运作 系统。对人类健康至关重要的是，免疫系统保持对微生物群的耐受性，保持 共生关系。限制针对微生物区系的病理免疫反应，对 微生物区系必须在生命早期建立。对共生微生物的耐受性下降可能导致 慢性炎症性疾病，如炎症性肠病、哮喘和皮炎。动态平衡与 微生物区系是通过产生在胸腺和胸腺中发育的抗原特异性调节性T细胞来实现的 和外围设备。接触微生物区系，特别是在新生儿期，被认为是至关重要的。 特雷格诱导。在人类和动物的疾病模型中都发现了这种成分 微生物区系的变化，也称为生物失调，与后续疾病易感性的增加有关 引发炎症疾病。值得注意的是，生命早期的变化被认为具有最重大的意义 对疾病易感性的影响。在动物模型中，用选定的肠道微生物定植对 疾病。目前还不清楚对微生物群的耐受性是如何实现的，而且，如果诱导 对肠道微生物的耐受性仅限于特定的早期生命发育窗口。使用鼠标模型 其T细胞受体识别肠道微生物，我们发现这种微生物在肠道的定植导致 选择特定于该生物体的T细胞。我们假设肠道抗原提呈细胞(APC) 遇到这些生物进入胸腺，在那里它们诱导T细胞选择。在目标1中 计划中的工作，我们将使用体内模型来定义特定微生物的引入如何导致 T细胞群。我们还将确定是否对T细胞发育有不同的影响，这取决于 在微生物定植发生的发展窗口。我们将进一步定义如果时间选择 特定微生物的定植促进或限制了炎症性疾病的发展。在《目标2》中我们将 定义微生物或微生物产物如何从肠道进入胸腺。我们将确定 这种微生物贩运所需的肠道细胞群以及定义转录图谱 允许T细胞选择。这将确定我们将能够操纵的路径，以限制或拯救 自身免疫的发展。

Project Summary Over the millennia humans have coevolved with a large number of microorganisms, collectively known as the microbiota, which provide many key signals that aid in the development and proper functioning of the immune system. It is vital to human health that the immune system remains tolerant to the microbiota maintaining a symbiotic relationship. To limit pathological immune responses against the microbiota, immune tolerance to the microbiota must be established early in life. A breakdown in tolerance to commensal microbes can result in chronic inflammatory disorders such as inflammatory bowel disease, asthma and dermatitis. Homeostasis with the microbiota is achieved by generation of antigen specific regulatory T cells that develop in both the thymus and periphery. Exposure to the microbiota, especially during the neonatal period is thought to be critical for this Treg induction. It has been found in humans as well as in animal models of disease, that compositional changes in the microbiota, also known as dysbiosis, correlate with increased susceptibility to subsequent induction of inflammatory disease. Notably, changes early in life are thought to have the most significant impact on disease susceptibility. In animal models, colonization with select intestinal microbes sensitizes to disease. It remains unclear how tolerance against the microbiota is achieved, and further, if the ability to induce tolerance to intestinal microbes is limited to a specific early life developmental window. Using a mouse model whose T cell receptor recognizes intestinal microbes, we find intestinal colonization with this microbe leads to selection of T cells specific for that organism. We hypothesize that intestinal antigen presenting cells (APCs) that encounter these organisms traffic to the thymus where they induce T cell selection. In Aim 1 of the proposed work, we will use in vivo models to define how introduction of specific microbes leads to alterations of T cell populations. We will also define whether there are differential impacts on T cell development depending on the developmental window of when microbial colonization occurs. We will further define if timing of colonization with select microbes promotes or limits development of inflammatory disease. In Aim 2 we will define how the microbe or microbial product travels from the intestine to the thymus. We will determine the intestinal cell population required for trafficking of this microbe as well as define transcriptional profiles that allow for T cell selection. This will identify pathways that we will be able to manipulate to limit or rescue from the development of autoimmunity.