Consequences of AhR activation in Dendritic Cells

描述（由申请人提供）：芳基烃受体（AhR）的激活已成为T细胞介导的免疫应答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活化化学物质不敏感，但T细胞介导的应答受到AhR活化的严重影响，并导致免疫功能障碍。树突状细胞（DC）在T细胞的活化和分化中起关键作用，并且由于DC组成性地表达显著水平的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。我们最近已经证明AhR激活的DC具有调节表型和功能，可以指导调节性T细胞（TCLs）的分化， 有效抑制抗原特异性免疫应答的产生。然而，诱导调节性DC的具体机制目前尚不清楚。此外，AhR可以结合到大量的化学品，天然的（即吲哚-3-甲醇和靛玉红）和人造的（即TCDD），和配体特异性的影响可能存在与耐受性潜力的DC的产生。定义DC中AhR激活的后果将显着促进我们对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活化产生直接诱导TcR的免疫调节细胞，最终导致主动免疫耐受。为了成功地测试这一假设，我们将确定由AhR激活的DC产生的产生TdR并诱导免疫抑制的调节元件（目的1）。然后，我们将描绘的信号转导事件的基础上诱导的调节介质产生的树突状细胞后AhR激活（目的2）。最后，我们将研究转移AhR激活的调节性DC以有意抑制抗原特异性免疫的治疗潜力（目的3）。除了挑战T细胞主要负责AhR激活的免疫调节作用的当前范式之外，这项研究将扩大我们对AhR激活如何产生能够影响T细胞介导的免疫应答的免疫调节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活化以产生用于治疗免疫介导的疾病的新治疗方法，并鉴定环境诱导的免疫功能障碍的生物标志物。

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.