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.
Dearstyne
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Department of Environmental and Molecular Toxicology and Environmental Health Sciences Center, Room 1007, Agricultural Life Sciences Building, Oregon State University, Corvallis, OR 97331, USA.
Kerkvliet
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D003864:Depression, Chemical; D004785:Environmental Pollutants / Q000633:toxicity*; D005434:Flow Cytometry; D007202:Indicators and Reagents; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010718:Phosphatidylserines / Q000096:biosynthesis; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D019014:fas Receptor / Q000276:immunology*
D017252:CD3 Complex; D004785:Environmental Pollutants; D007202:Indicators and Reagents; D010718:Phosphatidylserines; D000072317:Polychlorinated Dibenzodioxins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor