2,3,7,8-Tetrachlorodibenzo- p-dioxin modulates the expression of cKrox and Runx3, transcription regulatory factors controlling the lineage commitment of CD4 +CD8 + into CD4 and CD8 thymocytes, respectively

Abstract

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) was reported to skew the lineage commitment of thymocytes toward CD4 −CD8 + T (CD8 T) cells. However, the underlying mechanisms are not known. In the present study, we first demonstrated that the expression of transcription regulatory factors such as cKrox and Runx3, which have been shown to be intimately associated with the commitment of CD4 +CD8 + double-positive (DP) to CD4 or CD8 single-positive (SP) thymocyes, was down-regulated by TCDD in CD4 SP thymocytes, but up-regulated in DP, CD4 +CD8 + double-negative (DN), and CD8 SP thymocytes. Then, we found that TCDD inhibited the differentiation of DPK cells, an immature CD4 +CD8 + lymphoma cell line, into CD4 +CD8 − T cells, as well as the expression of cKrox and Runx3 upon antigen stimulation. Co-treatment with the AhR antagonist α-naphthoflavone did not completely block the inhibitory action of TCDD on DPK differentiation and the expression of cKrox and Runx3 in DPK cells, suggesting that the immunomodulatory abilities of TCDD are produced, at least in part, independently of the AhR pathway in DPK cells. Our findings could help in understanding the regulatory mechanisms of TCDD on thymocyte development, in particular on the skewed differentiation of DP into CD8 SP thymocytes.