Evidence for the promotion of positive selection of thymocytes by Ah receptor agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin

Abstract

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ligand for the arylhydrocarbon receptor (Ah receptor), abundant in the murine thymus. In the thymus immunocompetent T cells develop. Upon exposure of murine fetal thymi in organ cultures to TCDD the distribution of mature and immature thymocytes is skewed towards apparently mature, prospective cytotoxic cells of the CD4⁻CD8⁺T cell receptor⁺ phenotype. The normally abundant CD4⁺CD8⁺ cells are decreased. Proliferation of the most immature thymocyte subpopulations is inhibited and maturation of thymocytes appears accelerated by TCDD. Eventually the thymocyte number is significantly decreased. Selective treatment of stroma cells showed them to be the primary target cells of TCDD action. Thymus stroma plays a pivotal role in thymocyte maturation and is indispensable for the selection of thymocytes bearing T cell receptors specific for foreign antigen in the context of self. We tested whether the effects of TCDD on thymocyte differentiation and maturation has further consequences for the selection processes by analysing (a) the repertoire of V_β genes used as a measure for negative selection and (b) the expression of CD69 and bcl-2 by thymocytes as a parameter for positive selection. Our data indicate that TCDD does not cause gross disturbance of negative selection but provide evidence for more cells auditioning for positive selection by TCDD exposure.