ROLE OF AHR IN T LYMPHOCYTE DEVELOPMENT AND FUNCTION

AHR 在 T 淋巴细胞发育和功能中的作用

• 批准号: 9208952
• 负责人: Liang Zhou
• 金额: $ 30.79万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9208952
• 关键词: ROLE; AHR; LYMPHOCYTE; DEVELOPMENT; FUNCTION

 DESCRIPTION (provided by applicant): Regulatory T cells (Tregs) specified by the Forkhead transcription factor Foxp3 are important to suppress unwanted inflammatory responses in order to maintain immune homeostasis. The gut represents a specific microenvironment for Treg-mediated immune tolerance due to large amounts of antigens derived from food or microbiota, and proinflammatory cytokines produced by various immune cells. The aryl hydrocarbon receptor (Ahr) is an environmental sensor that detects not only xenobiotic ligands such as environmental pollutants (e.g., dioxin) but also physiological compounds generated by host cells, microbiota, and/or diet (e.g., amino acid tryptophan metabolites). The goal of the proposal is to understand the molecular regulation of Tregs by Ahr, a ligand-dependent transcription factor. Our preliminary data suggest that Ahr-expressing Tregs were preferentially enriched in the gut. Using an RNA-Seq approach, we showed that multiple genes that have been previously implicated in Treg cell development, maintenance, and function were perturbed by Ahr deficiency in Tregs. Using a T cell transfer model of colitis, we further showed that Tregs lacking expression of Ahr could not suppress disease in vivo. Using a combination of biochemical, molecular, and genetic approaches, in the proposal we will test the hypothesis that Ahr expression in Tregs plays a key role in gut immune homeostasis by regulating Treg cell development, maintenance, and/or function. Specifically, we will determine 1) the mechanism(s) underlying the enrichment of Ahr-expressing Tregs in the gut; 2) the molecular mechanism(s) by which Ahr regulates expression of the molecules that are involved in Treg development and maintenance; and 3) the in vivo role of Ahr in Tregs during gut inflammation and infection. These experiments will offer an opportunity to elucidate environmental impacts on immune tolerance via the Ahr-mediated pathway. Our study will provide novel cellular and molecular insights into the development and function of Tregs regulated by Ahr in a tissue- and cell-specific manner. Since Ahr is a ligand-dependent transcription factor and its activity can be modulated by small molecules, better understanding of the role of Ahr in Tregs may lead to development of novel therapeutic approaches by modulating Ahr expression and/or function in Tregs to treat autoimmunity and inflammation.

 描述（由申请人提供）：由叉头转录因子Foxp 3指定的调节性T细胞（TcR）对于抑制不需要的炎症反应以维持免疫稳态是重要的。肠道代表Treg介导的免疫耐受的特定微环境，这是由于大量来源于食物或微生物群的抗原以及各种免疫细胞产生的促炎细胞因子。芳烃受体（Ahr）是一种环境传感器，其不仅检测异生素配体如环境污染物（例如，二恶英）以及由宿主细胞、微生物群和/或饮食产生的生理化合物（例如，氨基酸色氨酸代谢物）。该提案的目标是了解配体依赖性转录因子Ahr对TcR的分子调控。我们的初步数据表明，表达Ahr的TcR优先富集在肠道中。使用RNA-Seq方法，我们发现先前与Treg细胞发育，维持和功能有关的多个基因被TcG中的Ahr缺陷所干扰。使用结肠炎的T细胞转移模型，我们进一步表明，缺乏T细胞的结肠炎患者， Ahr的表达在体内不能抑制疾病。使用生物化学，分子和遗传学方法的组合，在该提案中，我们将测试的假设，即在THEB中的Ahr表达通过调节调节Treg细胞的发育，维持和/或功能在肠道免疫稳态中起着关键作用。具体而言，我们将确定1）肠道中表达Ahr的Tcl 3富集的潜在机制; 2）Ahr调节参与Treg发育和维持的分子表达的分子机制;和3）肠道炎症和感染期间Ahr在Tcl 3中的体内作用。这些实验将提供一个机会，阐明通过Ahr介导的途径对免疫耐受的环境影响。我们的研究将提供新的细胞和分子的见解的发展和功能的TcR调节AHR在组织和细胞特异性的方式。由于Ahr是一种配体依赖性转录因子，其活性可以通过小分子调节，因此更好地了解Ahr在Treg中的作用可能会通过调节Treg中的Ahr表达和/或功能来开发新型治疗方法，以治疗自身免疫和炎症。