Regulation of T helper cell functions by aryl hydrocarbon receptor

项目摘要/摘要： 自身免疫性疾病总共影响了2300多万美国人，并造成了巨大的疾病负担。 许多自身免疫性疾病的特点是病理性的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细胞群在表型上有所不同，包括 T滤泡辅助(TFH)细胞，位于次级淋巴器官和T外周的滤泡中 辅助(TPH)细胞，这是B细胞辅助T细胞，迁移到发炎的周围组织，如 类风湿关节。TPH细胞和Tfh细胞共同具有通过产生B细胞来招募B细胞的能力 趋化因子CXCL13通过表面相互作用促进B细胞分化 分泌的细胞因子。调控TPH细胞和TFH细胞发育和功能的信号 自身免疫仍未完全描述，尤其是对T细胞的产生知之甚少。 CXCL13。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， 作为一种强有力的TPH和TFH细胞表型的负调节因子，具有显著的抑制T细胞的作用 CXCL13生产。在这个项目中，我们利用人类原代T细胞和患者样本来评估广泛的 AHR对TPH和TFH细胞发育、功能以及转录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，并寻求寻找新的转录 使用CRISPR阵列的AHR下游的调解器。此外，我们还将研究滑液和血清。 来自类风湿关节炎患者的样本和比较条件以评估改变的程度 AHR激动剂和拮抗剂活性在类风湿关节炎中的作用 TPH细胞在靶组织中的积聚。我们期待这个项目将揭示新的机制 通过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新的干扰策略 TPH和TFH细胞的治疗作用。

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.