Skewed differentiation of thymocytes toward CD8 T cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires activation of the extracellular signal-related kinase pathway

Abstract.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and its structural analogs are widespread environmental contaminants and highly toxic. TCDD is reported to reduce thymocyte numbers and skew the lineage commitment of thymocytes toward CD4^–CD8⁺ T (CD8 T) cells. The extracellular signal-related kinase (ERK) pathway has been suggested as critical for physiological thymocyte differentiation and apoptosis, and to be activated by TCDD in some types of cells. In the present study, we used a chemical inhibitor and mouse fetal thymus organ cultures (FTOCs) to investigate whether activation of the ERK pathway is involved in the TCDD-induced alteration of thymocytes. On days 4 and 6 of culture, the numbers of total cells and CD4⁺CD8⁺ (DP) cells were significantly decreased by TCDD. By contrast, the number of mature CD8 T cells was increased on day 4, confirming that TCDD induces differentiation to CD8 T cells. We then assessed the effects of U0126, an ERK pathway inhibitor, on the TCDD-induced alterations on day 4 of FTOC. The TCDD-induced increase in mature CD8 T cell number was not observed in the presence of the inhibitor, although total and DP cell reductions were not significantly affected. Furthermore, U0126 did not suppress the induction of CYP1A1 mRNA by TCDD in thymocytes of adult mice, confirming that the inhibitor does not suppress the activation of aryl hydrocarbon receptor. In conclusion, our results suggest that activation of the ERK pathway is required for TCDD-induced differentiation to mature CD8 T cells, but not for reduction of thymocyte numbers.