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

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

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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.

项目摘要/摘要：自身免疫性疾病统一影响了超过2300万美国人，并造成了巨大的疾病负担。许多自身免疫性疾病的特征是病理T细胞-B细胞相互作用和产生自动抗体。帮助B细胞自身免疫性疾病的T细胞群体在表型中有所不同，包括 T卵泡辅助器（TFH）细胞，该细胞驻留在继发性淋巴器官的卵泡中，t外周助手（TPH）细胞，它们是B细胞棘手T细胞，迁移到发炎的外周组织，例如类风湿关节。 TPH细胞和TFH细胞具有通过生产B细胞募集B细胞的能力化学吸引剂CXCL13，然后通过表面相互作用和分泌的细胞因子。调节TPH细胞和TFH细胞中发育和功能的信号自身免疫性仍未完全描述，尤其是关于T细胞产生的知之甚少 CXCL13。我们的初步数据揭示了芳基烃受体（AHR），配体门控转录因子，作为TPH和TFH细胞表型的有效负调节剂，对抑制T细胞具有巨大的作用 CXCL13生产。在这个项目中，我们利用人类原代T细胞和患者样品来评估广泛的 AHR对TPH和TFH细胞发育，功能以及转录组和表观遗传调节的影响。我们将通过CHIP-SEQ评估人类T细胞中AHR的直接靶标，并寻求识别新的转录使用CRISPR阵列下游的介体。此外，我们将研究滑液和血清来自类风湿关节炎和比较疾病患者的样本，以评估范围的改变类风湿关节炎中AHR激动剂和拮抗剂活性，这种疾病以丰富的特征 TPH细胞在目标组织中的积累。我们希望这个项目将揭示新的机制由AHR介导的，该AHR调节CXCL13的产生以及TFH和TPH细胞表型的关键特征。了解这些关键T细胞功能的分子控制可能会突出显示干扰的新策略 TPH和TFH细胞治疗。