Consequences of AhR activation in Dendritic Cells

树突状细胞中 AhR 激活的后果

• 批准号: 8977199
• 负责人: David M Shepherd
• 金额: $ 1.6万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8977199
• 关键词: Address; Adverse effects; Affect; Antigen-Presenting Cells; Antigens; Aryl Hydrocarbon Receptor; Binding; Biochemical; Biological; Biological Markers; Cell Shape; Cells; Cellular biology; Chemicals; Dendritic Cells; Development; Diet; Dioxins; Disease; Drug Targeting; Elements; Environmental Pollutants; Environmental Pollution; Event; Exposure to; Gene Targeting; Generations; Goals; Health; Human; Immune; Immune System Diseases; 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; Regulation; Regulatory Element; Regulatory T-Lymphocyte; Research; Response Elements; Role; Signal Pathway; Signal Transduction; Steroids; T cell differentiation; T-Lymphocyte; Testing; Tetrachlorodibenzodioxin; Therapeutic; Tretinoin; Tryptophan 2,3 Dioxygenase; activating transcription factor; adaptive immunity; allergic response; aryl hydrocarbon receptor ligand; cell mediated immune response; chronic autoimmune disease; immunoregulation; immunotoxicity; improved; in vivo; indirubin; innovation; interest; man; novel; novel strategies; novel therapeutic intervention; research study; response; therapeutic target; transcription factor

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）：芳基烃受体（AhR）的激活已成为T细胞介导的免疫反应和免疫介导的疾病发展中的重要事件。尽管初始 T 细胞主要对 AhR 激活化学物质不敏感，但 T 细胞介导的反应会受到 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发挥着关键作用，并且由于 DC 持续表达显着水平的 AhR，因此它们对 AhR 配体特别敏感。因此，DC 代表了在暴露于能够激活 AhR 的化合物后能够介导免疫调节作用的关键细胞群。我们最近证明，AhR 激活的 DC 具有调节表型和功能，可以指导调节性 T 细胞 (Treg) 和 有效抑制抗原特异性免疫反应的产生。然而，诱导调节性树突状细胞的具体机制目前尚不清楚。此外，AhR可以结合大量的化学物质，包括天然的（即吲哚-3-甲醇和靛玉红）和人造的（即TCDD），并且配体特异性效应可能存在于产生具有耐受性潜力的DC。定义 DC 中 AhR 激活的后果将显着增进我们对 DC 如何控制 T 细胞分化的理解。因此，本提案的目标是检验中心假设，即 DC 中的 AhR 激活会产生免疫调节细胞，直接诱导 Tregs，最终导致主动免疫耐受。为了成功检验这一假设，我们将确定 AhR 激活的 DC 产生的调节元件，这些元件可生成 Tregs 并诱导免疫抑制（目标 1）。然后，我们将描述在 AhR 激活后诱导 DC 产生的调节介质的信号传导事件（目标 2）。最后，我们将研究转移 AhR 激活的调节性 DC 来有意抑制抗原特异性免疫的治疗潜力（目标 3）。除了挑战当前 T 细胞主要负责 AhR 激活的免疫调节作用的范式之外，这项研究还将扩大我们对 AhR 激活如何产生能够影响 T 细胞介导的免疫反应的免疫调节 DC 的理解。这项研究将对 AhR 和 DC 生物学领域产生强大而持续的影响，并将展示如何操纵 AhR 激活来产生治疗免疫介导疾病的新治疗方法，并识别环境引起的免疫功能障碍的生物标志物。