Polycyclic aromatic hydrocarbons (PAH) and related halogenated hydrocarbons are environmental chemicals present at high concentrations in Superfund hazardous waste sites. These compounds induce cancer, suppress the immune system, and modulate cell growth. At least some, if not all of these responses are mediated by the aryl hydrocarbon receptor (AhR), a cytosolic protein that is converted into a DNA-binding transcription factor following ligand binding. Although primarily known for its regulation of PAH-metabolizing enzymes, the AhR regulates transcription of several genes and appears to affect cell cycle control. AhR activation by environmental chemicals during embryogenesis results in multiple cycle control. AhR activation by environmental chemicals during embryogenesis results in multiple developmental defects. Studies with AhR/null mice suggest that the absence of the AhR also disrupts organ development, indicating that the AhR plays an important role in development even in the absence of exogenous ligands. This conclusion is supported by our demonstration of abnormal T lymphocyte development in AhR transgenic (AhR/TG) mice. Furthermore, AhR up- regulation accompanies antigen-specific human T cell stimulation suggesting a role for the AhR in T cell activation and a mechanism through which AhR ligands may affect antigen-specific immune responsiveness. Given these observations, we have postulated that the AhR plays a role in T cell development and that inappropriate AhR activation by environmental chemicals compromises T cell maturation and function.
Three specific aims have been proposed to test this hypothesis and to define factors which control human AhR expression: 1. Define the mechanism responsible for T cell developmental defects in AhR transgenic mice. Using AhR/TG mice produced in our laboratory and AhR/null mice we will determine if the AhR influences deletion of autoreactive clones in the thymus and/or T cell activation and control in secondary lymphoid organs. 2. Determine the role of the AhR in environmental chemical-induced immunosuppression. AhR/TG mice will be used as a highly sensitive system for screening potentially immunotoxic environmental chemicals and as an optimal model for defining the mechanism(s) through which these chemicals mediate immune suppression. 3. Define transcription factors regulating AhR gene expression during activation of primary human peptide specific CD8+ T cells. Having demonstrated AhR up-regulation in human T and B lymphocytes, we will use molecular biology techniques to map regulatory regions in the AhR promoter and to define factors which control AhR transcription. Collectively, results obtained will shed light on the physiological role of the AhR during T cell maturation and on the consequences of AhR ligand exposure during T cell development and activation.
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