T cell Tolerance to Enteric Commensal Bacteria

T 细胞对肠道共生细菌的耐受性

• 批准号: 10299254
• 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/10299254
• 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; 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.

项目概要 胃肠道被大量生活在其中的共生细菌定殖。 与主人和谐相处。这对免疫系统提出了挑战，免疫系统必须促进耐受性 有益细菌种类，同时仍提供针对致病菌种类的保护。确实，崩溃 这种歧视被认为是炎症性肠病（IBD）的一个主要原因。 与自身抗原不同，源自共生微生物群的抗原不太可能出现在 胸腺影响中枢 T 细胞耐受性。相反，对这些抗原的特异性耐受必须完全依赖于 在肠道免疫环境中起作用的外周机制。然而，这些机制和 它们介导的耐受性的质量尚不清楚。为了更好地研究这些过程，我们的实验室 开发的肽：MHCII 四聚体试剂使我们能够直接识别罕见的肠道 CD4+ T 细胞 对小鼠体内几种不同共生细菌物种的免疫显性表位具有特异性。我们的 初步研究支持缺失、Treg 和 Tr1 细胞发育的不同作用，具体取决于细菌 物种。更好地解析共生抗原特异性 T 细胞表型以及 由于这些表型在整个抗原特异性群体中的异质性，我们结合使用 四聚体与单细胞 RNA-seq 转录组学全面定义表型和克隆 不同共生抗原特异性 CD4+ T 细胞群内的异质性。 该项目的首要目标是了解 T 细胞维持免疫的机制 对胃肠道特定共生细菌的耐受性，以便它们最终可以被 为达到治疗目的而进行操纵。我们假设对共生细菌抗原的耐受性是 由多个 CD4+ T 细胞命运维持，每个细胞都做出独特但重叠的功能贡献 面对动态的肠道环境，共同建立持久的耐受性。我们将检验这个假设 1) 定义共生细菌抗原特异性 CD4+ T 细胞的发育命运，这些细胞有助于 免疫耐受，2) 表征共生抗原特异性调节 T 细胞亚群的功能。