Microbiota Specific T Cell Selection

项目摘要 数千年来，人类与大量微生物共同进化，这些微生物统称为 微生物群，提供许多关键信号，有助于免疫系统的发育和正常功能。 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， 共生关系为了限制针对微生物群的病理性免疫反应，对微生物群的免疫耐受性 微生物群必须在生命早期建立。对肠道微生物的耐受性下降会导致 慢性炎性疾病如炎性肠病、哮喘和皮炎。稳态， 微生物群通过产生抗原特异性调节性T细胞来实现， 和外围。暴露于微生物群，特别是在新生儿时期，被认为是至关重要的 Treg诱导。在人类和动物疾病模型中发现， 微生物群的变化，也称为生态失调，与对随后的疾病的易感性增加有关。 诱发炎性疾病。值得注意的是，生命早期的变化被认为是最重要的 影响疾病易感性。在动物模型中，选择的肠道微生物的定殖使以下敏感： 疾病目前尚不清楚如何实现对微生物群的耐受性，以及进一步地，是否能够诱导 对肠道微生物的耐受性限于特定的早期生命发育窗口。使用小鼠模型 它的T细胞受体识别肠道微生物，我们发现这种微生物的肠道定植导致 选择对该生物体特异的T细胞。我们假设肠道抗原呈递细胞（APC） 它们会运输到胸腺，在那里它们诱导T细胞选择。在目标1中， 建议的工作，我们将使用体内模型来定义如何引入特定的微生物导致的改变， T细胞群体。我们还将确定是否有不同的影响T细胞的发展， 在微生物定植发生的发育窗口上。我们将进一步确定， 选择的微生物的定殖促进或限制炎性疾病的发展。在目标2中， 确定微生物或微生物产物如何从肠道进入胸腺。康贝特人将以 运输这种微生物所需肠细胞群以及定义转录谱， 允许T细胞选择。这将确定我们将能够操纵以限制或拯救的途径 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.