T cell Tolerance to Enteric Commensal Bacteria

T 细胞对肠道共生细菌的耐受性

• 批准号: 10424555
• 负责人: James J Moon
• 金额: $ 50.24万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-09 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10424555
• 关键词: Antigens; Autoantigens; Bacteria; Bacterial Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cellular biology; Clonal Deletion; Collection; Complex; Development; Discrimination; Disease; Economic Burden; Enteral; Environment; Excision; FOXP3 gene; Future; Gastrointestinal tract structure; Goals; Health; Heterogeneity; Immune; Immune Tolerance; Immune response; Immune system; Immunodominant Epitopes; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Knowledge; Longevity; Lymphocyte; Mediating; Memory; Mus; Pathogenesis; Pathogenicity; Pathway interactions; Peptides; Peripheral; Persons; Phenotype; Population; Process; Property; Reagent; Regulatory Pathway; Regulatory T-Lymphocyte; Reporter Genes; Resolution; Role; Shapes; Societies; Specificity; System; T cell clonality; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Thymus Gland; Transgenic Organisms; antigen-specific T cells; base; commensal bacteria; commensal microbes; cytotoxic; enteric infection; gastrointestinal system; gut microbiota; intestinal epithelium; intraepithelial; novel strategies; single-cell RNA sequencing; social; transcriptomics

PROJECT SUMMARY The gastrointestinal tract is colonized by an enormous collection of commensal bacteria living in harmony with the host. This poses a challenge for the immune system which must promote tolerance to beneficial bacteria species while still providing protection against pathogenic species. Indeed, a breakdown in such discrimination is thought to be a major underlying cause of inflammatory bowel disease (IBD). Unlike self-antigens, antigens derived from commensal microbiota are unlikely to be presented in the thymus to impact central T cell tolerance. Rather, specific tolerance to these antigens must rely exclusively on peripheral mechanisms acting within the immune environment of the gut. However, these mechanisms and the quality of the tolerance they mediate are unclear. To better investigate these processes, our lab has developed peptide:MHCII tetramer reagents that enable us to directly identify rare gut CD4+ T cells with specificity to immunodominant epitopes from several different commensal bacteria species in mice. Our preliminary studies support varied roles for deletion, Treg, and Tr1 cell development depending on the bacteria species. To provide better resolution of commensal antigen-specific T cell phenotypes as well as the heterogeneity of these phenotypes within the overall antigen-specific population, we are combining our use of tetramers with single cell RNA-seq transcriptomics to comprehensively define phenotypic and clonal heterogeneity within distinct commensal antigen-specific CD4+ T cell populations. The overarching goal of this project is to understand the mechanisms by which T cells maintain immune tolerance to specific commensal bacteria of the gastrointestinal tract so that they may ultimately be manipulated for therapeutic benefit. We hypothesize that tolerance to commensal bacterial antigens is maintained by multiple CD4+ T cell fates, each making unique but overlapping functional contributions that collectively establish durable tolerance in the face of the dynamic gut environment. We will test this hypothesis by 1) defining developmental fates for commensal bacterial antigen-specific CD4+ T cells that contribute to immune tolerance, and 2) characterizing the function of commensal antigen-specific regulatory T cell subsets.

项目摘要 胃肠道通过居住在 与主持人和谐。这对免疫系统构成了挑战，必须促进宽容 有益的细菌物种，同时仍能保护致病物种。确实，崩溃了 这种歧视被认为是炎症性肠病（IBD）的主要根本原因。 与自我抗原不同，来自共生微生物群的抗原不太可能在 胸腺影响中央T细胞的耐受性。相反，对这些抗原的特定耐受性必须仅依靠 作用在肠道免疫环境内的外围机制。但是，这些机制和 它们介导的公差质量尚不清楚。为了更好地调查这些过程，我们的实验室有 开发的肽：MHCII四聚体试剂，使我们能够直接鉴定稀有的肠道CD4+ T细胞 来自小鼠的几种不同共生细菌的免疫主流表位的特异性。我们的 初步研究支持删除，TREG和TR1细胞发育的各种作用，具体取决于细菌 物种。为了更好地解决共生抗原特异性T细胞表型以及 这些表型在整体抗原特异性人群中的异质性，我们正在结合使用 具有单细胞RNA-seq转录组学的四聚体可全面定义表型和克隆 不同共同抗原特异性CD4+ T细胞种群中的异质性。 该项目的总体目标是了解T细胞保持免疫的机制 对胃肠道特定的共生细菌的耐受性，以最终可能是 为治疗益处而操纵。我们假设对共生细菌抗原的耐受性是 由多个CD4+ T细胞命运保持 面对动态肠道环境，共同建立耐用的耐受性。我们将检验这个假设 1）定义有助于有助于的共生细菌抗原特异性CD4+ T细胞的发育命运 免疫耐受性和2）表征共生抗原特异性调节T细胞亚群的功能。