Microbiota Specific T Cell Selection

微生物群特异性 T 细胞选择

• 批准号: 10308400
• 负责人: Matthew Bettini
• 金额: $ 34.24万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-03 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308400
• 关键词: Animal Disease Models; Animal Model; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antigens; Asthma; Autoantigens; Autoimmune Diseases; Autoimmunity; Automobile Driving; Bacteria; Benign; CD8-Positive T-Lymphocytes; Cells; Cellularity; Chronic; Clinical Research; Colitis; Data; Dendritic Cells; Dermatitis; Detection; Development; Disease; Disease Progression; Disease susceptibility; Equilibrium; Exposure to; FOXP3 gene; Gastrointestinal tract structure; Gene Expression Profile; Generations; Germ-Free; Gnotobiotic; Grant; Health; Homeostasis; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Inflammatory; Inflammatory Bowel Diseases; Insulin-Dependent Diabetes Mellitus; Intestines; Lamina Propria; Life; Link; Maintenance; Microbe; Modeling; Molecular; Mucous Membrane; Multiple Sclerosis; Mus; Organism; Pathologic; Pathology; Pathway interactions; Peripheral; Population; Predisposition; Regulatory T-Lymphocyte; Respiratory System; Rodent; Role; Self Tolerance; Shapes; Signal Transduction; Site; Skin; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Thymocyte Development; Thymus Gland; Tissues; Travel; Work; antigen-specific T cells; atopy; chemokine receptor; commensal bacteria; commensal microbes; dysbiosis; gut colonization; gut microbiota; host microbiota; immune health; immune system function; in vivo Model; lymphoid structures; member; microbial; microbial colonization; microbiota; microorganism; mouse model; neonatal exposure; neonatal period; pathogen; response; trafficking; urogenital tract

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.

项目摘要 在千年中，人类已经与大量的微生物共同发展 微生物群，它提供了许多关键信号，可帮助免疫的发展和正常功能 系统。免疫系统对人类健康至关重要 共生关系。为了限制对微生物群的病理免疫反应，免疫耐受性 必须在生命的早期建立微生物群。对共生微生物的公差破裂可能会导致 慢性炎症性疾病，例如炎症性肠病，哮喘和皮炎。稳态 微生物群是通过在两种胸腺中发展的抗原特异性调节细胞来实现的 和外围。暴露于微生物群中，尤其是在新生儿时期，对此至关重要 Treg诱导。它在人类以及疾病的动物模型中都发现了它。 菌群的变化，也称为营养不良，与随后的敏感性增加相关 诱导炎症性疾病。值得注意的是，生活的早期变化被认为是最重要的 对疾病易感性的影响。在动物模型中，具有精选肠道微生物的定殖敏感 疾病。目前尚不清楚如何实现对微生物群的耐受性，进一步 对肠道微生物的耐受性仅限于特定的早期生命发展窗口。使用鼠标模型 其T细胞受体识别肠道微生物，我们发现使用这种微生物的肠道定植会导致 选择特有该生物的T细胞。我们假设肠道抗原呈递细胞（APC） 这些生物会遇到这些生物传播到胸腺诱导T细胞选择的地方。在目标1中 提议的工作，我们将使用体内模型来定义特定微生物的引入如何导致变化 T细胞种群。我们还将定义是否对T细胞开发产生差异影响 在发生微生物定植的发育窗口上。我们将进一步定义时间是否 精选微生物定植会促进或限制炎症性疾病的发展。在目标2中，我们将 定义微生物或微生物产物如何从肠道到胸腺。我们将确定 贩运该微生物所需的肠细胞种群以及定义转录曲线 允许选择T细胞。这将确定我们将能够操纵以限制或从中营救的途径 自身免疫的发展。