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.

项目摘要/摘要 有几条证据表明T细胞与克罗恩病的发病有关，克罗恩病是一种未受控制的 肠道的一种炎症状态，免疫细胞对生活在那里的细菌反应过度。 以前对克罗恩病的抗原非特异性T细胞的研究还没有发现在 他们可以解释这种反应过度的现象。然而，我们最近发现了免疫的CD4T细胞 一种能与由这样一种细菌(大肠杆菌)产生的蛋白质抗原(OMPC)中的多肽发生反应的系统，对其 抗体通常只出现在克罗恩病患者身上。我们发现这些OMPC特异性细胞 产生IL-10，除非他们来自克罗恩病患者，并假设这种缺陷在 在克罗恩病炎症中的作用。IL-10是一种细胞因子，显然在限制 肠道炎症，因为没有IL-10基因的小鼠和出生时携带IL-10基因突变的人类 IL-10的受体都会迅速发展成严重的小肠结肠炎，类似于克罗恩病。的总目标是 这里提出的研究是为了确定为什么这些肠道菌群抗原特异的T细胞无法在 克罗恩病，是一种在这种情况下对肠道菌群失去耐受性的机制。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学分析，我们可以 用MHC-II四聚体分离。这一假说将在全基因组范围内以两个特定的目标来解决 AIM 1的表达差异与IL-10的表达相关，并为失败的IL-10的表观遗传学基础 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的理解 克隆氏病患者肠道微生物抗原特异性T细胞对IL-10的异常调节 为确定这种缺陷如何导致疾病发病机制奠定了基础。