Immunotoxicity of TCDD: role of Fas expression and MHC phenotype on TCDD-mediated thymic artophy and decrease in peripheral T cell responsiveness

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is well known for its immunotoxic effects particularly on the thymus as well as on T and B lymphocyte functions. Previous studies have suggested that TCDD may induce apoptosis in thymocytes although its demonstration in vivo has met with limited success. TCDD has also been shown to alter the major histocompatibility complex (MHC)-encoded molecules, however, its role in immunotoxicity is not clear. In this study, we investigated the role of Fas (CD95), an important molecule involved in the induction of apoptosis, on TCDD-mediated immunotoxicity using mice bearing homozygous lpr mutation which leads to failure of expression of Fas. When TCDD was administered orally at 0, 0.1, 1.0, or 5.0 pg/kg body weight for 11 days, it was found to be less toxic to the thymocytes from C57BL/6 lpr/lpr mice (Ah-responsive, Fas⁻) when compared to C57BL/6 +/+ mice (Ah-responsive, Fas⁺). Similar results were obtained when peripheral T cell responsiveness to antigenic challenge with conalbumin was studied in these mice. When mice that differed only at the MHC were compared for immunotoxic effects of TCDD, it was noted that B10.D2 (Ah-responsive, H-2ᵈ) were more sensitive to TCDD-mediated thymic atrophy and peripheral T cell dysfunction when compared to B10 mice (Ah-responsive, H-2ᵇ). In all TCDD-sensitive strains tested, the thymic atrophy was accompanied by a uniform depletion of all four subsets of T cells (CD4⁺, CD4⁺CD8⁺, CD4⁻CD8⁻, and CD8⁺). Furthermore, in these strains, TCDD suppressed the antigen-specific peripheral T cell responsiveness but not the responsiveness of naive resting T cells to polyclonal mitogens. Lastly, using cell-mixing experiments, it was demonstrated that TCDD directly affected the T cells responding to conalbumin but not the antigen presenting cells (APCs). Together our studies demonstrate that although Ah locus plays the primary role determining the toxicity of TCDD on the T cells, there are secondary factors such as expression of Fas or the MHC-phenotype which may play an important role in TCDD-mediated immunotoxicity. The role of Fas further suggests that TCDD may induce toxicity in T cells by triggering apotosis.