Early life regulation of microbiota specific thymic T cell development

微生物群特异性胸腺 T 细胞发育的早期生命调节

• 批准号: 10568756
• 负责人: Matthew Bettini
• 金额: $ 82.97万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-07 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568756
• 关键词: Adult; Affinity; Age; Antigens; Asthma; Autoantigens; Autoimmune Diseases; Autoimmunity; Automobile Driving; CD8-Positive T-Lymphocytes; Cell physiology; Cells; Characteristics; Chronic; Communities; Cues; Data; Dendritic Cells; Dermatitis; Development; Disease; Education; Ensure; Environment; Epithelial Cells; Equilibrium; Exposure to; FOXP3 gene; Human; Hypersensitivity; Immune; Immune system; Immunity; Infection; Inflammatory; Inflammatory Bowel Diseases; Intestines; Life; Microbe; Modeling; Molecular; Mucous Membrane; Mus; Nutrient; Organ; Pathology; Pathway interactions; Peripheral; Play; Predisposition; Process; Publishing; Regulation; Regulatory T-Lymphocyte; Role; Self Tolerance; Series; Shapes; Signal Induction; Signal Transduction; System; T-Cell Development; T-Lymphocyte; Thymocyte Development; Thymus Gland; Time; Tissues; Work; age related; antigen-specific T cells; autoreactive T cell; cell motility; early life exposure; effector T cell; fighting; gut microbiota; immune function; in vivo Model; intestinal epithelium; microbial; microbial products; microbiome; microbiota; microorganism; microorganism antigen; migration; novel; pathogen; response; thymus transplantation; trafficking

Project Summary Early life exposure to environments rich in microbial products corresponds with a more diverse microbiota and significantly decreases susceptibility to developing asthma and atopic sensitization. However, it is unclear how this early life exposure supports proper immune function. In recently published data, we find thymic expansion of microbiota specific T cells in early life. This is driven by microbiota carrying intestinal dendritic cells migration from the intestine to the thymus. We hypothesize specific microbial signals in intestinal environment in young mice, including signaling downstream of microbe attachment to intestinal epithelial cells, encourages intestinal DC trafficking to thymus. In the thymus, we hypothesize these microbes serve as a template to ensure expansion of microbe specific T cells, offering protection from pathogen challenge. Understanding these specific microbial derived signals, as well as unique thymic environmental cues during early life will allow us to understand this novel pathway. In Aim 1 of the proposed work, we will use in vivo models to understand the role for the intestine in this system, identifying molecular signals activating thymic migration of intestinal DCs. In Aim 2 we will determine the thymic signals that allow for thymic expansion of microbiota specific T cell. We will determine whether gut migratory APCs regulate selection or expansion of microbiota specific T cells. Finally, will determine whether migration is restricted by the age of the thymus or intestine environment through a series of thymic transplant studies. These mechanistic studies will help identify pathways that we will be able to manipulate to alter thymic T cell development and limit or rescue from the development of inflammatory disease.

项目摘要 生命早期暴露于富含微生物产物的环境对应于更多样化的微生物群， 显著地降低了发生哮喘和特应性致敏的易感性。然而，目前还不清楚如何 这种早期的生活接触支持适当的免疫功能。在最近发表的数据中，我们发现胸腺扩张 在生命早期的微生物群特异性T细胞。这是由携带肠道树突状细胞迁移的微生物群驱动的 从肠道到胸腺我们假设年轻人肠道环境中的特定微生物信号 小鼠，包括肠道上皮细胞微生物附着的下游信号， DC运输至胸腺。在胸腺中，我们假设这些微生物作为模板， 微生物特异性T细胞，提供保护免受病原体的挑战。了解这些特定的微生物 衍生的信号，以及在生命早期独特的胸腺环境线索将使我们能够理解这一点， 新途径。在拟议工作的目标1中，我们将使用体内模型来了解肠道的作用 在该系统中，识别激活肠DC的胸腺迁移的分子信号。在目标2中， 确定允许微生物群特异性T细胞的胸腺扩增的胸腺信号。我们将确定 肠道迁移性APC是否调节微生物群特异性T细胞的选择或扩增。最后，将决定 迁移是否受到胸腺年龄或肠道环境的限制，通过一系列胸腺 移植研究这些机制研究将有助于确定我们能够操纵的途径， 改变胸腺T细胞发育并限制或挽救炎症性疾病的发展。