Consequences of AhR Activation in Dendritic Cells

描述(申请人提供)：芳香烃受体(AhR)介导一大类环境污染物的毒性效应，卤代芳香烃。此外，免疫系统是典型的AhR配体2，3，7，8-四氯二苯并-对二恶英(TCDD)的非常敏感的目标。TCDD诱导的免疫功能障碍的特点是T细胞介导的免疫功能受到严重抑制，疾病易感性增加。树突状细胞(DC)具有诱导T细胞活化、扩增和分化的功能，被认为是TCDD的直接靶点。TCDD激活AhR后，DC异常表达关键的共刺激分子，并过早地从免疫组织中缺失。因此，我们假设树突状细胞中AhR的激活导致其激活和/或存活的缺陷，并最终有助于抑制获得性免疫。本实验室的重点是了解AhR配体诱导的强大免疫抑制的细胞和分子基础，而这一提议的主要目标是确定TCDD诱导的DC功能抑制的机制。这些目标将由以下四个特定目标确定：(1)确定AhR激活在DC的命运和功能中的作用；(2)确定AhR激活在DC中的作用是否完全通过二恶英反应元件(ORE)介导；(3)研究Fas/Fas配体通路和细胞周期扰动在AhR介导的DC死亡中的作用。这项申请中提出的研究将对人类健康产生重大的积极影响。这项工作将促进我们对DC与抗原特异性T细胞相互作用的基本理解。它将确定异种生物诱导的免疫毒性的机制，并可能确定产生耐受性DC的新的治疗方法。

DESCRIPTION (provided by applicant): The Aryl hydrocarbon receptor (AhR) mediates the toxic effects of a broad class of environmental contaminants, the halogenated aromatic hydrocarbons. Moreover, the immune system is a very sensitive target of the prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD-induced immune dysfunction is characterized by profound suppression of T cell-mediated immunity and increased susceptibility to disease. Dendritic cells (DC) that function to induce the activation, expansion and differentiation of T cells are postulated to be direct targets of TCDD. DC aberrantly express critical costimulatory molecules and undergo premature deletion from immune tissues following AhR activation by TCDD. Therefore, we hypothesize AhR activation in DC causes defects in their activation and/or survival and ultimately contributes to the suppression of adaptive immunity. The focus of this laboratory is to understand the cellular and molecular basis for the potent immune suppression induced by AhR ligands, while the primary objective of this proposal is to determine the mechanisms underlying TCDD-induced suppression of DC functions. These objectives will be determined by the following four Specific Aims: (1) to define the role of AhR activation in the fate and function of DC; (2) to determine if the effects of AhR activation in DC are mediated exclusively via the Dioxin Response Element (ORE); and (3) to investigate the involvement of the Fas/Fas ligand pathway and cell cycle perturbation in AhR-mediated DC death. The research proposed in this application will have significant, positive effects on human health. This work will advance our basic understanding of DC interactions with antigen-specific T cells. It will define mechanisms of xenobiotic-induced immunotoxicity, and may identify novel therapeutic approaches to generate tolerogenic DC.