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

基本信息

批准号：
10558631
负责人：
James Daniel Lord
金额：
$ 21.66万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
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/10558631
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&apos 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 Genomics Genotype Goals Homeostasis Human IL10 gene Immune Immune Tolerance Immune system Immunoglobulin A Immunology Individual Inflammation Inflammatory Inflammatory Bowel Diseases Institution Interleukin-10 Intestines Measures Modeling Molecular Mus Mutation Pathogenesis Patients Peptides Persons Phenotype Play Positioning Attribute Production Proteins Qualifying Reaction Regulation Research Research Personnel Rest Role Sampling Systemic Therapy T cell regulation T-Lymphocyte Technology Translational Research Work antigen-specific T cells biobank cohort cytokine genome-wide gut inflammation gut microbiome gut microbiota high dimensionality high reward insight interleukin-10 receptor microbiome microorganism antigen novel strategies prevent prospective recruit response transcriptome sequencing transcriptomics

项目摘要

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.

项目概要/摘要多项证据表明 T 细胞与克罗恩病的发病机制有关，克罗恩病是一种不受控制的疾病肠道炎症，免疫细胞对肠道细菌反应过度。先前对克罗恩病中抗原非特异性 T 细胞的研究尚未发现他们可以解释这一过度反应。然而，我们最近发现了免疫系统的 CD4 T 细胞该系统可以与一种此类细菌（大肠杆菌）产生的蛋白抗原 (OmpC) 中的肽发生反应，抗体通常仅见于克罗恩病患者。我们发现这些 OmpC 特异性细胞除非它们来自克罗恩病患者，否则会产生 IL-10，并假设这种缺陷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，在限制肠道炎症，因为没有 IL-10 基因的小鼠和出生时就有 IL-10 基因突变的人类 IL-10 受体均会迅速发展为严重的小肠结肠炎，类似于克罗恩病。总体目标为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性 T 细胞无法在体内产生 IL-10 克罗恩病是一种在这种情况下失去对肠道菌群耐受性的机制。新颖的方法是将单细胞基因表达和表观遗传分析整合到这些 OmpC 特异性 T 细胞中，我们可以与 MHC-II 四聚体分离。该假设将在全基因组范围内的两个具体目标中得到解决表达差异与目标 1 中的 IL-10 表达相关，以及失败的 IL-10 的表观遗传基础克罗恩病中的表达将在目标 2 中揭示。这些研究将共同推进我们的理解克罗恩病中肠道微生物抗原特异性 T 细胞对 IL-10 的异常调节，并提供为确定这种缺陷如何导致疾病发病机制奠定了基础。