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Consequences of AhR activation in Dendritic Cells

树突状细胞中 AhR 激活的后果

基本信息

批准号：
9278170
负责人：
David M Shepherd
金额：
$ 70.98万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9278170
关键词：
Acute Address Adverse effects Affect Antigen-Presenting Cells Antigens Aryl Hydrocarbon Receptor Autoimmune Diseases Binding Biochemical Biological Biological Markers Cell Shape Cells Cellular biology Chemicals Chronic Dendritic Cells Development Diet Dioxins Disease Drug Targeting Elements Environmental Pollutants Environmental Pollution Event Exposure to FOXP3 gene Gene Targeting Generations Goals Health Human Immune Immune System Diseases Immune System and Related Disorders Immune Tolerance Immune response Immune system Immunity Immunosuppression Immunosuppressive Agents In Vitro Indole-3-Carbinol Inflammatory Knowledge Lead Ligands Mediating Mediator of activation protein Molecular Mus Pathway interactions Phenotype Physiological Play Population Process Production Receptor Activation Receptor Cell Regulation Regulatory Element Regulatory T-Lymphocyte Research Response Elements Role Signal Pathway Signal Transduction Steroids T cell differentiation T-Cell Development T-Lymphocyte Testing Tetrachlorodibenzodioxin Therapeutic Toxicology Tretinoin Tryptophan 2,3 Dioxygenase adaptive immune response allergic response aryl hydrocarbon receptor ligand cell mediated immune response experimental study immunoregulation immunotoxicity improved in vivo indirubin innovation interest man novel novel marker novel strategies novel therapeutic intervention public health relevance response targeted treatment transcription factor

项目摘要

DESCRIPTION (provided by applicant): Activation of the Aryl hydrocarbon receptor (AhR) has emerged as a significant event in the development of T cell-mediated immune responses and immune-mediated diseases. Despite the fact that naive T cells are predominantly insensitive to AhR-activating chemicals, T cell-mediated responses are acutely affected by AhR activation and contribute to immune dysfunction. Dendritic cells (DCs) play a critical role in the activation and differentiation of T cells and because DCs constitutively express significant levels of AhR, they are especially sensitive to AhR ligands. Therefore, DCs represent a critical cell population capable of mediating the immunomodulatory effects following exposure to compounds capable of activating the AhR. We have recently demonstrated that AhR-activated DCs possess a regulatory phenotype and function that can direct differentiation of regulatory T cells (Tregs) and effectively suppress the generation of antigen-specific immune responses. However, the specific mechanisms underlying the induction of regulatory DCs are currently unknown. Moreover, the AhR can bind to a vast array of chemicals, both natural (ie indole-3-carbinol and indirubin) and man-made (ie TCDD), and ligand-specific effects may exist for the generation of DCs with tolerogenic potential. Defining the consequences of AhR activation in DCs will significantly advance our understanding of how DCs control T cell differentiation. Therefore, the goal of this proposal is to test the central hypothesis that AhR activation in DCs generates immunoregulatory cells that directly induce Tregs ultimately leading to active immunologic tolerance. To successfully test this hypothesis, we will determine the regulatory elements produced by AhR-activated DCs that generate Tregs and induce immune suppression (Aim 1). We will then delineate the signaling events underlying the induction of regulatory mediators produced by DCs following AhR activation (Aim 2). Finally, we will investigate the therapeutic potential of transferring AhR-activated regulatory DCs to intentionally suppress antigen-specific immunity (Aim 3). In addition to challenging the current paradigm that T cells are primarily responsible for the immunomodulatory effects of AhR activation, this research will expand our understanding of how AhR activation generates immunoregulatory DCs capable of influencing T cell-mediated immune responses. This research will have a powerful and sustained impact on the fields of AhR and DC biology, and will demonstrate how AhR activation may be manipulated to yield novel therapeutic approaches for the treatment immune- mediated diseases and identify biomarkers of environmentally induced immune dysfunction.

描述（由申请人提供）：芳烃受体（AhR）的激活已经成为T细胞介导的免疫反应和免疫介导疾病发展中的一个重要事件。尽管初始T细胞主要对AhR激活化学物质不敏感，但T细胞介导的反应受到AhR激活的严重影响，并导致免疫功能障碍。树突状细胞（dc）在T细胞的激活和分化中起着关键作用，由于dc组成性地表达显著水平的AhR，它们对AhR配体特别敏感。因此，dc代表了一个关键的细胞群，能够在暴露于能够激活AhR的化合物后介导免疫调节效应。我们最近已经证明ahr激活的dc具有调节性表型和功能，可以指导调节性T细胞（Tregs）和