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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：
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
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/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&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 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

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.

项目总结/文摘