T cells upon activation undergo apoptosis, a process termed activation-induced cell death (AICD). In the current study, we investigated whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases AICD and whether this constitutes one of the mechanisms by which TCDD induces immunotoxicity. To this end, C57BL/6+/+, C57BL/6 gld/gld (Fas ligand-defective) and C57BL/6 lpr/lpr (Fas-deficient) mice were injected with TCDD (50 microg/kg body weight, ip) or the vehicle (corn oil) and with anti-CD3 mAbs into the footpads. 3 days later, inguinal and popliteal lymph node cells were harvested, pooled and enumerated. Cells were cultured in vitro with anti-CD3 mAbs and cell proliferation was measured. Also, such cells were studied for their ability to undergo apoptosis upon in vitro culture with either tissue culture medium alone or with anti-CD3 mAbs. The data demonstrated that lymph nodes from TCDD-treated wild-type (+/+) mice showed a decrease in cellularity and the T cells exhibited decreased responsiveness to anti-CD3 mAbs when compared to the vehicle-treated control group. Furthermore, such cells from TCDD-treated mice exhibited increased levels of apoptosis upon in vitro culture when compared to the cells from vehicle-treated mice. In contrast, activated lymph nodes from TCDD-treated C57BL/6 gld/gld and C57BL/6 lpr/lpr mice showed normal cellularity and T cell responsiveness to anti-CD3 stimulation when compared to the vehicle controls. In addition, the activated lymph node T cells from the TCDD-treated C57BL/6 gld/gld and C57BL/6 lpr/lpr mice failed to exhibit increased apoptosis when compared to the controls. The current study demonstrates that the immunotoxic effects of TCDD in activated peripheral T cells may result from increased AICD mediated through Fas-Fas ligand interactions.