T cell Tolerance to Enteric Commensal Bacteria

项目总结 胃肠道内寄生着大量共生细菌。 与主人和睦相处。这对免疫系统构成了挑战，免疫系统必须促进对 有益的细菌物种，同时仍提供对致病物种的保护。事实上，中国经济的崩溃 这种歧视被认为是炎症性肠病(IBD)的主要潜在原因。 与自身抗原不同，来自共生微生物区系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性必须完全依赖于 作用于肠道免疫环境内的外周机制。然而，这些机制和 他们调停的容忍程度如何尚不清楚。为了更好地研究这些过程，我们的实验室已经 开发的多肽：MHCII四聚体试剂，使我们能够直接识别罕见的肠道CD4+T细胞 小鼠体内几种不同共生细菌的免疫优势表位的特异性。我们的 初步研究支持缺失、Treg和TR1细胞发育的不同角色取决于细菌 物种。为了更好地分辨共生抗原特异的T细胞表型以及 这些表型在整个抗原特异性人群中的异质性，我们正在结合我们的使用 用单细胞RNA-SEQ转录组的四聚体综合定义表型和克隆性 不同共生抗原特异性的CD4+T细胞群体中的异质性。 这个项目的首要目标是了解T细胞维持免疫的机制 对胃肠道特定共生菌的耐受性，以便它们最终可能 为了治疗的好处而操控。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，集体建立持久的容忍度。我们将检验这一假设 通过1)确定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，以及2)共生抗原特异性调节性T细胞亚群的功能特征。

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.