Mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced decrease in anti-CD3-activated CD4(+) T cells: the roles of apoptosis, Fas, and TNF.
The environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), suppresses T cell functions and reduces T cell numbers in multiple models of immune stimulation. However, the underlying mechanism(s) by which TCDD induces these changes has yet to be elucidated. We hypothesized that TCDD affects T cells through the induction or augmentation of apoptosis. In these studies, we used antibody to CD4, annexin V, and 7-AAD in three-color flow cytometric analyses to examine the relationship between the decrease in CD4(+) T cells and cell death in mice treated with anti-CD3 and TCDD. In addition, we examined two signaling pathways, Fas and TNF, in order to elucidate a potential mechanism by which TCDD increases cell death. Our results show that the TCDD-induced decrease in CD4(+) T cell number correlated with an increase in the percentage of dead cells, but not with cells expressing an early apoptotic phenotype. The TCDD-induced decrease in CD4(+) T cells was attenuated in Fas- and FasL-deficient mice (lpr and gld, respectively), but not by treatment with a neutralizing antibody to TNF. While these results suggest that the Fas pathway may be important in TCDD-induced T cell death, however, the effect of TCDD on the Fas pathway remains unclear. Taken together, our data suggest that TCDD-induced suppression of CD4(+) T cells involves, in part, increased cell death that may be mediated by Fas/FasL interaction.