Consequences of AhR Activation in Dendritic Cells

描述（由申请人提供）：芳基烃受体（AhR）介导一大类环境污染物（卤代芳香烃）的毒性作用。此外，免疫系统是原型 AhR 配体 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 的非常敏感的靶标。 TCDD 诱导的免疫功能障碍的特点是 T 细胞介导的免疫受到严重抑制并增加对疾病的易感性。树突状细胞 (DC) 具有诱导 T 细胞激活、扩增和分化的作用，被认为是 TCDD 的直接靶标。 DC 异常表达关键共刺激分子，并在 TCDD 激活 AhR 后从免疫组织中过早缺失。因此，我们假设 DC 中的 AhR 激活会导致其激活和/或存活缺陷，并最终导致适应性免疫的抑制。该实验室的重点是了解 AhR 配体诱导的有效免疫抑制的细胞和分子基础，而该提案的主要目标是确定 TCDD 诱导的 DC 功能抑制的机制。这些目标将由以下四个具体目标决定： (1) 定义 AhR 激活在 DC 的命运和功能中的作用； (2) 确定 DC 中 AhR 激活的影响是否仅通过二恶英反应元件 (ORE) 介导； (3) 研究 Fas/Fas 配体途径和细胞周期扰动在 AhR 介导的 DC 死亡中的参与。本申请中提出的研究将对人类健康产生重大、积极的影响。这项工作将增进我们对 DC 与抗原特异性 T 细胞相互作用的基本了解。它将定义异生素诱导的免疫毒性的机制，并可能确定产生耐受性 DC 的新治疗方法。

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.