Graduate Thesis Or Dissertation
 

Investigations into the mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced immune suppression: effects on dendritic cell phenotype and function

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  • T cell-dependent immune responses are highly sensitive to suppression by exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), yet direct effects of TCDD on T cells have been difficult to demonstrate. Because the activation of naive T cells is initiated by dendritic cells (DC), the studies presented in this dissertation were designed to test the hypothesis that TCDD affects these antigen-presenting cells in a manner which ultimately results in suppressed T cell activation. The expression of numerous cell surface proteins known to be important in signaling T cells to proliferate and differentiate was evaluated on splenic DC from C57B1/6 and Balb/c mice. The production of IL-12 and the ability of DC to activate allogeneic and antigen-specific T cells were also tested. Contrary to expectation, exposure to TCDD resulted in enhanced expression of several accessory molecules including B7-2, CD40, ICAM-1, CD24 and the major histocompatibility complex (MHCII). In contrast, expression of LFA-1 was significantly decreased on DC from TCDD-treated mice. These effects were dose-dependent, persisted for at least 14 days, and did not occur in aryl hydrocarbon receptor (AhR)-deficient mice. Interestingly, TCDD treatment also decreased the numbers of DC recovered from the spleen by day 7 following exposure in C57B1/6 mice and by day 3 in Balb/c animals. When T cells were cultured with DC from TCDD-treated mice, the proliferative response of the T cells and the production of IL-2, IL-4, and IFN-γ was not suppressed but instead tended to be increased. DC production of IL-12 was also enhanced. Furthermore, TCDD did not interfere with the ability of DC to internalize latex beads or to activate antigen-specific T cells, suggesting that uptake and processing of antigen by DC is not impaired by TCDD. AhR message was detected in splenic DC and AhR protein was found in two DC cell lines, indicating that DC may be directly affected by TCDD. Taken together, these results suggest that TCDD provides an activation stimulus to DC and may lead to their premature deletion. The relationship between these effects and TCDD-induced immune suppression remains to be determined.
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