The studies proposed in this renewal application represent a continuation of ongoing studies to understand the role of CD4+T cell activation in the immunotoxic effects of 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD). Data obtained during the current grant period are consistent with the hypothesis that TCDD suppresses the allogeneic CTL and allantibody responses through a defect in T helper cell activity. Furthermore, current data indicate that TCDD exposure suppresses CD4+ T helper cell function by influencing the activation signals they receive from antigen-presenting cells (APC). Specifically, we have shown that TCDD exposure reduces the expression of B7 molecules on the surface on macrophages and B cells, which provide critical co-stimulatory signals necessary for full T cell activation. Consistent with the consequences of incomplete co-stimulation, we have evidence to suggest that activated CD4+ cells die instead of proliferating and differentiating into effector cells subsequent to TCDD exposure. The hypothesis to be tested in this renewal application is that T cell unresponsiveness to primary antigenic stimulation in TCDD-treated mice is due to T cell deletion resulting from defective co-stimulation by APC. We further hypothesize that toxicity is initiated in the APC by increased oxidative stress resulting from TCDD exposure. The alteration in intracellular redox balance results in partially activated APCs that are unable to provide the necessary co- stimulatory signals to T cells. The lack of generation of sufficient T cell help is the cause of suppressed immune responsiveness in TCDD-treated mice. This hypothesis will be tested by characterizing: (1) the fate of antigen-activated T cells in TCDD-treated mice; and (2) the influence of TCDD exposure on the redox state and co-stimulatory functions of APC. The proposed studies include an evaluation of oxidant production by APC, antioxidant status of APC based on measurements of glutathione and thioredoxin, expression in nitric oxide synthases, and activation of NF- kappaB. In addition, studies will determine in antioxidant treatment prevents TCDD-induced T cell apoptosis and immunosuppression. A new focus of the proposed studies is on dendritic cells, which represent the most potent APC for the activation of naive T cells. Comparative effects of TCDD on the intracellular redox status and antigen-presenting functions of macrophages and B cells will be examined as these cells play important accessory roles in sustaining the responsiveness of activated T cells. These studies will help to elucidate the mechanisms of immune suppression mediated by TCDD, an environment contaminant of concern to human health, as well as the prototypic ligand of the Ah receptor. These studies will provide insight into the natural role of this widely expressed receptor.
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