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: 10179018
• 负责人: Deepak Angara Rao
• 金额: $ 39.22万
• 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/10179018
• 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 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; Infrastructure; Insulin-Dependent Diabetes Mellitus; Interruption; Joints; Ligands; Lupus; Lymphoid Follicle; Measures; Mediating; Mediator of activation protein; Methods; Modification; Molecular; Pathologic; Patients; Pattern; Peripheral; Pharmacology; Phenotype; Plasmablast; Play; Population; Production; Psoriatic Arthritis; Receptor Activation; Receptor Inhibition; Regulation; Regulator Genes; 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; burden of illness; cytokine; effector T cell; epigenetic regulation; exhaust; exhaustion; monocyte; novel; recruit; repository; response; secondary lymphoid organ; seropositive; single-cell RNA sequencing; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; tumor

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： 自身免疫性疾病共同影响了超过 2300 万美国人，并带来了巨大的疾病负担。 许多自身免疫性疾病的特征是病理性 T 细胞-B 细胞相互作用和产生 自身抗体。在自身免疫性疾病中帮助 B 细胞的 T 细胞群的表型各不相同，包括 滤泡辅助 T (Tfh) 细胞，存在于次级淋巴器官的滤泡中，以及外周 T 细胞 辅助 (Tph) 细胞，它们是 B 细胞辅助 T 细胞，可迁移到发炎的外周组织，例如 类风湿关节。 Tph 细胞和 Tfh 细胞都具有通过产生 B 细胞来招募 B 细胞的能力 趋化剂 CXCL13，然后通过表面相互作用和促进 B 细胞分化 分泌的细胞因子。调节 Tph 细胞和 Tfh 细胞发育和功能的信号 自身免疫的描述仍然不完整，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碳氢化合物受体（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 细胞具有显着效果 CXCL13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控的影响。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因子 使用 CRISPR 阵列检测 AHR 下游的介质。此外，我们还将研究滑液和血清 类风湿关节炎患者和对照病症的样本，以评估程度的变化 类风湿性关节炎中 AHR 激动剂和拮抗剂活性的研究，这种疾病的特征是大量的 Tph 细胞在靶组织中积累。我们期望这个项目将揭示新的机制 由 AHR 介导，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干扰的新策略 Tph 和 Tfh 细胞具有治疗作用。