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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

基本信息

批准号：
9319753
负责人：
Liang Zhou
金额：
$ 39.33万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
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/9319753
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 FOXP3 gene Food GPR15 gene 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 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 experimental study forkhead protein genetic approach gut microbiota in vivo insight interleukin-22 microbiome microbiota mouse model novel novel therapeutic intervention novel therapeutics public health relevance receptor expression sensor small molecule tool transcription factor transcriptome sequencing

项目摘要

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.