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.
The objectives of this novel proposal are to determine how activation of the Aryl hydrocarbon receptor (AhR) in dendritic cells (DCs) results in the generation of immunosuppressive regulatory T cells, the signaling mechanisms involved in this process, and how AhR activation in DCs may be manipulated to yield novel therapeutic approaches for the treatment of immune- mediated diseases such as allergic responses, autoimmune disease and chronic inflammatory disease. Studies proposed to evaluate exposure of DCs to both environmental and dietary AhR ligands may also identify novel biomarkers of exposure to immunotoxic chemicals that may lead to enhanced regulation of environmental contaminants, and identify significant new approaches to maintain optimal health via modulation of the immune system. !
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