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Regulation of T helper cell functions by aryl hydrocarbon receptor

芳烃受体对 T 辅助细胞功能的调节

基本信息

批准号：
10596640
负责人：
Deepak Angara Rao
金额：
$ 37.5万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-18 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10596640
关键词：
Affect Agonist American Architecture Arthritis Aryl Hydrocarbon Receptor Autoantibodies Autoimmune Diseases Autoimmune Hepatitis Autoimmunity B cell differentiation B-Lymphocytes BCL6 gene BLR1 gene Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CRISPR/Cas technology CXCL13 gene Celiac Disease Cell Aggregation Cell Communication Cell Differentiation process Cell physiology Cells ChIP-seq Chemotactic Factors Clustered Regularly Interspaced Short Palindromic Repeats Data Degenerative polyarthritis Development Disease Epigenetic Process Fibroblasts Frequencies Gene Targeting Generations Genes Genetic Genetic Transcription Genomics Goals Helper-Inducer T-Lymphocyte Human Immune System Diseases Infiltration Infrastructure Insulin-Dependent Diabetes Mellitus Interruption Joints Ligands Lupus Lymphoid Follicle Measures Mediating Mediator Methods Modification Molecular Pathologic Patients Pattern Peripheral Phenotype Plasmablast Play Population Production Psoriatic Arthritis Receptor Activation Receptor Inhibition Regulation Reporter Reporting Rheumatoid Arthritis Role Sampling Serum Signal Transduction Source Structure of germinal center of lymph node Surface Synovial Fluid Synovial Membrane Systemic Scleroderma T cell differentiation T-Lymphocyte T-Lymphocyte Subsets Techniques Testing Therapeutic Tissues Tonsil Work antagonist burden of illness cancer infiltrating T cells cell motility cytokine effector T cell epigenetic regulation exhaust exhaustion interleukin-21 monocyte novel pharmacologic recruit repository response secondary lymphoid organ seropositive single-cell RNA sequencing transcription factor transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract: Autoimmune diseases collectively affect over 23 million Americans and impose a huge burden of disease. Many autoimmune diseases are characterized by pathologic T cell-B cell interactions and production of autoantibodies. The T cell populations that help B cells in autoimmune diseases vary in phenotype and include T follicular helper (Tfh) cells, which reside in follicles of secondary lymphoid organs, as well as T peripheral helper (Tph) cells, which are B cell-helper T cells that migrate to inflamed peripheral tissues such as the rheumatoid joint. Tph cells and Tfh cells share the ability to recruit B cells via production of a B cell chemoattractant CXCL13 and then promote B cell differentiation through both surface interactions and secreted cytokines. The signals that regulate development and function of Tph cells and Tfh cells in autoimmunity remain incompletely described, and particularly little is known about T cell production of CXCL13. Our preliminary data reveal the aryl hydrocarbon receptor (AHR), a ligand-gated transcription factor, as a potent negative regulator of Tph and Tfh cell phenotype, with a dramatic effect on suppressing T cell CXCL13 production. In this project, we utilize human primary T cells and patient samples to evaluate the broad effects of AHR on Tph and Tfh cell development, function, and transcriptomic and epigenetic regulation. We will evaluate the direct targets of AHR in human T cells via ChIP-seq and seek to identify new transcriptional mediators downstream of AHR using CRISPR arrays. In addition, we will study synovial fluid and serum samples from patients with rheumatoid arthritis and comparator conditions to evaluate alterations in the extent of AHR agonist and antagonist activity in rheumatoid arthritis, a disease characterized by abundant accumulation of Tph cells in the target tissue. We expect that this project will reveal novel mechanisms mediated by AHR that regulate production of CXCL13 and key features of Tfh and Tph cell phenotypes. Understanding the molecular control of these key T cell functions may highlight new strategies to interfere with Tph and Tfh cells therapeutically.

项目总结/文摘: