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

• 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
• 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

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.

项目概要/摘要： 自身免疫性疾病共同影响超过2300万美国人，并造成巨大的疾病负担。 许多自身免疫性疾病的特征在于病理性T细胞-B细胞相互作用和免疫球蛋白的产生。 自身抗体在自身免疫性疾病中帮助B细胞的T细胞群在表型上不同，包括 T滤泡辅助细胞（Tfh），位于次级淋巴器官的滤泡中，以及T外周淋巴细胞 辅助性（Tph）细胞，其是迁移到发炎的外周组织（例如，淋巴细胞）的B细胞辅助性T细胞。 类风湿关节炎Tph细胞和Tfh细胞都具有通过产生B细胞来募集B细胞的能力 趋化因子CXCL 13，然后通过表面相互作用促进B细胞分化， 分泌的细胞因子。调节Tph细胞和Tfh细胞的发育和功能的信号在 自身免疫性仍然没有完全描述，特别是对T细胞产生的自身免疫性知之甚少。 CXCL 13.我们的初步数据揭示了芳烃受体（AHR），一种配体门控转录因子， 作为Tph和Tfh细胞表型的有效负调节剂，对抑制T细胞增殖具有显著作用。 CXCL 13生产。在这个项目中，我们利用人类原代T细胞和患者样本来评估广泛的 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的直接靶点，并寻求识别新的转录因子。 使用CRISPR阵列检测AHR下游的介导物。此外，我们将研究滑液和血清 类风湿性关节炎患者和对照疾病患者的样本，以评估 AHR激动剂和拮抗剂活性在类风湿性关节炎，一种疾病的特点是丰富的 Tph细胞在靶组织中的积累。我们希望这个项目能够揭示新的机制， 由AHR介导，调节CXCL 13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新的策略，以干扰 Tph和Tfh细胞治疗。