CONSEQUENCES OF AhR-MEDIATED SIGNALING IN DENDRITIC CELLS

University Of Montana, Missoula MT

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Abstract

The Aryl hydrocarbon receptor (AhR) has been demonstrated to mediate most, if not all, of the toxic effects of a broad class of environmental contaminants, the halogenated aromatic hydrocarbons (HAHs). Many of these chemicals that include the dioxins, furans, and polychlorinated biphenyls (PCBs) persist for very long periods of time in the environment and have the potential to affect multiple target organs at very low doses. Moreover, the immune system has been shown to be one of the most sensitive targets for the prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD-induced immune dysfunction is characterized by a profound suppression of T cell-mediated immune responses although no direct TCDD effects have been shown to occur in T ceils. Rather, dendritic cells (DC) that function to provide a coordinated series of signals to induce the activation, expansion and differentiation of T cells are postulated to be targets of TCDD. Recent reports demonstrate that DC aberrantly express critical costimulatory molecules and undergo premature deletion from immune tissues following TCDD exposure. Therefore, we hypothesize that direct effects of TCDD on DC cause defects in their activation and/or survival and ultimately contribute to the suppression of adaptive immunity. The long-term goal of this laboratory is to understand the cellular and molecular basis for the potent immune suppression induced by AhR ligands. To advance toward this goal, the objectives of this proposal are: (1) to determine the role of the AhR in TCDDinduced DC dysfunction, and (2) to determine the mechanistic basis for the suppression of specific DC functions following exposure to TCDD. These objectives will be achieved in the context of four Specific Aims: (1) to track the activation and survival of DC during the generation of an antigen-specific T cell-mediated immune response in vivo and to directly evaluate the role of AhR activation on these endpoints, (2) to determine if the effects of AhR activation in DC are mediated exclusively via the Dioxin Response Element (DRE), (3) to investigate the involvement of the Fas/Fas ligand pathway in AhR-mediated DC dysfunction, and (4) to investigate the involvement of IL-12 in AhR-mediated DC dysfunction. The research proposed in this application will have significant, positive effects on human health on two levels. Firstly, this work will expand our understanding of the potential risks associated with exposure to the environmentally persistent halogenated aromatic hydrocarbons. Secondly, this work will provide the cornerstone for understanding the molecular and cellular functions of the AhR in dendritic cells, the primary immune cells involved in the initiation ofT cell-mediated adaptive immune responses.