ROLE OF FAS APOPTOSIS AND MHC GENES IN 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD)-INDUCED IMMUNOTOXICITY OF T-CELLS

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is well known for its immun otoxic effects particularly on the thymus as well as on T and B lympho cyte functions. Previous studies have suggested that TCDD may induce a poptosis in thymocytes although its demonstration in vivo has met with limited success. TCDD has also been shown to alter the major histocom patiblity complex- (MHC) encoded molecules, however, its role in immun otoxicity is not clear. In the current study, we investigated the role of Fas (CD95), an important molecule involved in the induction of apo ptosis, on TCDD-mediated immunotoxicity using mice bearing homozygous lpr mutation which leads to failure of expression of Fas. When TCDD wa s administered orally at 0, 0.1, 1.0, or 5.0 mu g/kg body weight for 1 1 days, it was found to be less toxic to the thymocytes from C57BL/6 l pr/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 stud ied in these mice, When mice that differed only at the MHC were compar ed for immunotoxic effects of TCDD, it was noted that B10.D2 (Ah-respo nsive, H-2(d)) were more sensitive to TCDD-mediated thymic atrophy and peripheral T cell dysfunction when compared to B10 mice (Ah-responsiv e, H-2(b)). In all TCDD-sensitive strains tested, the thymic atrophy w as accompanied by a uniform depletion of all four subset of T cells (C D4(+), CD4(+)CD8(+), CD4(-)CD8(-), and CD8(+)) and the percentage of t hese subsets was not altered, Furthermore, in these strains, TCDD supp ressed the antigen-specific peripheral T cell responsiveness but not t he responsiveness of naive resting T cells to polyclonal mitogens. Las tly, using cell-mixing experiments, it was demonstrated that TCDD dire ctly affected the T cells responding to conalbumin but not the antigen presenting cells (APCs). Together, our studies demonstrate that altho ugh 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.