Characterization of E. coli-specific T cells in Crohn's disease

克罗恩病中大肠杆菌特异性 T 细胞的表征

• 批准号: 10452471
• 负责人: James Daniel Lord
• 金额: $ 25.95万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452471
• 关键词: Address; Anti-Inflammatory Agents; Antibodies; Antigen Receptors; Antigens; Bacteria; CD4 Positive T Lymphocytes; Cells; Chromatin; Chromatin Structure; Chronic Disease; Clinic; Colon; Core Facility; Crohn' s disease; Data Set; Defect; Disease; Enterocolitis; Epigenetic Process; Equilibrium; Escherichia coli; Escherichia coli Proteins; Exploratory/Developmental Grant; Foundations; Funding; Future; Gastroenterology; Gastrointestinal tract structure; Gene Expression; Genes; Genomics; Genotype; Goals; Hepatitis B e Antigens; Homeostasis; Human; Immune; Immune Tolerance; Immune system; Immunoglobulin A; Immunology; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Institutes; Institution; Interleukin-10; Intestines; Measures; Modeling; Molecular; Mus; Mutation; Pathogenesis; Patients; Peptides; Persons; Phenotype; Play; Positioning Attribute; Production; Proteins; Reaction; Regulation; Research; Research Personnel; Rest; Role; Sampling; Systemic Therapy; T cell regulation; T-Lymphocyte; Technology; Translational Research; Work; antigen-specific T cells; base; biobank; cohort; cytokine; genome-wide; gut inflammation; gut microbiome; gut microbiota; high dimensionality; high reward; insight; microbiome; microorganism antigen; novel strategies; prevent; prospective; receptor; recruit; response; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Several lines of evidence have implicated T cells in the pathogenesis of Crohn's disease, an uncontrolled inflammatory condition of the intestines in which immune cells overreact to the bacteria that live there. Previous studies of antigen-nonspecific T cells in Crohn's disease have not identified overall differences in them that would explain this over reactivity. However, we have recently identified CD4 T cells of the immune system that can react to a peptide from protein antigen (OmpC) made by one such bacteria (E. coli), to which antibodies are commonly seen only in people with Crohn's disease. We found that these OmpC-specific cells make IL-10 unless they come from Crohn's disease patients, and hypothesize that this defect plays a central role in the inflammation of Crohn's disease. IL-10 is a cytokine that clearly plays a central role in limiting inflammation in the intestines, because mice without the IL-10 gene and humans born with a mutation in the receptor for IL-10 both quickly develop severe enterocolitis, resembling Crohn's disease. The overall goal of the studies proposed here is to determine why these gut flora antigen-specific T cells fail to make IL-10 in Crohn's disease, as a mechanism by which tolerance to gut flora is lost in this condition. The novel approach is to integrate single cell gene expression and epigenetic analyses in these OmpC-specific T cells we can isolate with MHC-II tetramers. The hypothesis will be addressed in two Specific Aims with genome-wide expression differences correlated with IL-10 expression in Aim 1, and an epigenetic basis for failed IL-10 expression in Crohn's disease to be revealed in Aim 2. Together these studies will advance our understanding of abnormal IL-10 regulation by gut microbial antigen-specific T cells in Crohn's disease, and provide the foundation for determining how such a defect contributes to disease pathogenesis.

项目总结/摘要 几条证据表明T细胞参与了克罗恩病的发病机制，克罗恩病是一种无法控制的疾病， 肠道的炎症状态，免疫细胞对肠道内的细菌反应过度。 以前对克罗恩病中抗原非特异性T细胞的研究尚未确定 他们可以解释这种过度反应。然而，我们最近发现了免疫系统中的CD 4 T细胞， 可以与来自蛋白质抗原（OmpC）的肽反应的系统（E.大肠杆菌），其中 抗体通常只在克罗恩病患者中可见。我们发现这些OmpC特异性细胞 除非它们来自克罗恩病患者，否则它们不会产生IL-10，并假设这种缺陷在克罗恩病患者中起着核心作用。 在克罗恩病炎症中的作用。IL-10是一种细胞因子，其在限制肿瘤细胞增殖中明显起着核心作用。 肠道炎症，因为没有IL-10基因的小鼠和出生时具有IL-10基因突变的人类， IL-10受体的受试者都迅速发展为严重的小肠结肠炎，类似于克罗恩病。的总目标 这里提出的研究是要确定为什么这些肠道植物群抗原特异性T细胞不能产生IL-10， 克罗恩病，作为一种机制，其中耐受肠道植物群是在这种情况下失去。这种新方法 是在这些OmpC特异性T细胞中整合单细胞基因表达和表观遗传分析， 用MHC-II四聚体分离。这一假设将在两个特定的目的与全基因组 表达差异与Aim 1中IL-10表达相关，以及IL-10失败的表观遗传基础 在克罗恩病中的表达将在Aim 2中揭示。这些研究将共同推进我们对 肠道微生物抗原特异性T细胞对克罗恩病中IL-10的异常调节， 确定这种缺陷如何有助于疾病发病机制的基础。