Consequences of AhR activation in Dendritic Cells

描述(由申请人提供)：芳香烃受体(AhR)的激活已经成为T细胞介导的免疫反应和免疫介导的疾病发展中的一个重要事件。尽管幼稚的T细胞对AhR激活的化学物质主要不敏感，但T细胞介导的反应受到AhR激活的强烈影响，并导致免疫功能障碍。树突状细胞(DCs)在T细胞的活化和分化中起着关键作用，由于DCs结构性地表达大量AhR，它们对AhR配体特别敏感。因此，树突状细胞代表了一个关键的细胞群体，能够在接触能够激活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具有调节表型和功能，可以指导调节性T细胞(Tregs)和 有效抑制抗原特异性免疫反应的产生。然而，诱导调节性DC的具体机制目前尚不清楚。此外，AhR可以与多种化学物质结合，既有天然的(如吲哚-3-甲醇和靛玉红)，也有人工的(如TCDD)，在产生具有耐受潜力的DC时可能存在配体特异性的效应。明确树突状细胞中AhR激活的后果将极大地促进我们对树突状细胞如何控制T细胞分化的理解。因此，这项提议的目的是验证这一中心假设，即树突状细胞中AhR的激活产生免疫调节细胞，直接诱导Tregs，最终导致主动免疫耐受。为了成功验证这一假设，我们将确定AhR激活的DC产生的调节元件，这些DC产生Tregs并诱导免疫抑制(目标1)。然后，我们将描绘在AhR激活后DC产生的调节介质的诱导下的信号事件(目标2)。最后，我们将研究转移AhR激活的调节性DC以故意抑制抗原特异性免疫的治疗潜力(目标3)。除了挑战目前认为T细胞主要负责AhR激活的免疫调节效应的范式外，这项研究还将扩大我们对AhR激活如何产生免疫调节DC的理解，这些DC能够影响T细胞介导的免疫反应。这项研究将对AhR和DC生物学领域产生强大和持续的影响，并将展示AhR激活如何被操纵以产生治疗免疫介导性疾病的新的治疗方法，并识别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.