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: 9028639
• 负责人: Liang Zhou
• 金额: $ 3.05万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9028639
• 关键词: Ablation; Amino Acids; Antigens; Aryl Hydrocarbon Receptor; Autoimmunity; Bacterial Infections; Biochemical; Biological; Biology; CCR6 gene; Cells; Citrobacter rodentium; Colitis; Communicable Diseases; Cues; Data; Development; Diet; Dioxins; Disease; Environment; Environmental Impact; Environmental Pollutants; Food; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Homeostasis; Homing; Human; Immune; Immune Tolerance; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Interferon Type II; Interleukin-17; Intestinal Diseases; Intestines; Lead; Ligands; Link; Lymphoid Cell; Maintenance; Maps; Mediating; Modeling; Molecular; Molecular Genetics; Molecular Mechanisms of Action; Mus; Nutrient; Pathogenesis; Pathway interactions; Patients; Phenotype; Physiological; Play; Production; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Signal Pathway; Specific qualifier value; T-Cell Development; T-Lymphocyte; Testing; Tissues; Transcriptional Regulation; Tryptophan; Up-Regulation; Xenobiotics; base; clinically relevant; cytokine; forkhead protein; genetic approach; gut microbiota; in vivo; insight; interleukin-22; microbiome; mouse model; novel; novel therapeutic intervention; public health relevance; receptor expression; research study; sensor; small molecule; tool; transcription factor; transcriptome sequencing

 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 under the steady state; 2) the molecular mechanism(s) by which Ahr regulates expression of the genes 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Forkhead转录因子Foxp3指定的调节性T细胞(Treg)对于抑制不必要的炎症反应以维持免疫稳态非常重要。肠道代表了Treg介导的免疫耐受的特定微环境，这是由于来自食物或微生物区系的大量抗原以及各种免疫细胞产生的促炎细胞因子。芳香烃受体(Ahr)是一种环境传感器，它不仅能检测环境污染物(如二恶英)等外来生物配体，还能检测由宿主细胞、微生物区系和/或饮食产生的生理化合物(如氨基酸色氨酸代谢物)。该提案的目的是了解配体依赖的转录因子AhR对Tregs的分子调控。我们的初步数据表明，表达AhR的Tregs优先在肠道中浓缩。使用RNA-Seq方法，我们证明了先前与Treg细胞的发育、维持和功能有关的多个基因受到Treg中AhR缺乏的干扰。使用结肠炎的T细胞转移模型，我们进一步表明Tregs缺乏 在体内，AhR的表达不能抑制疾病。在该提案中，我们将结合生化、分子和遗传学方法来检验这一假设，即AhR在Treg中的表达通过调节Treg细胞的发育、维持和/或功能在肠道免疫动态平衡中发挥关键作用。具体地说，我们将确定1)稳定状态下表达AhR的Treg在肠道中丰富的机制(S)；2)AhR调节Treg发育和维持相关基因表达的分子机制(S)；以及3)AhR在肠道炎症和感染过程中在Treg中的体内作用。这些实验将提供一个机会，通过Ahr介导的途径阐明环境对免疫耐受的影响。我们的研究将提供新的细胞和分子洞察力，以组织和细胞特异性的方式调控Tregs的发育和功能。由于AhR是一种配体依赖的转录因子，其活性可以被小分子调节，因此对AhR在Tregs中的作用的深入了解可能会导致通过调节Tregs中AhR的表达和/或功能来治疗自身免疫和炎症的新的治疗方法的发展。