We have used anti-T cell monoclonal antibodies (mAbs) as mimic ligands to study the effects of T cell receptor (TCR) ligation of cloned T helper type 1 cells in the presence or absence of accessory cells. Our results demonstrate that ligation of the TCR in the absence of accessory cells rapidly induces cell death. Cell death can be prevented by addition of spleen adherent cells, leading to strong clonal expansion. Induced cell death is inhibited by cyclosporin A and by anti-interferon gamma (IFN-gamma), and is restored by adding exogenous recombinant IFN-gamma to cyclosporin A-treated cells. These results demonstrate that IFN-gamma plays a critical role in cell death induced by anti-TCR mAbs in the absence of costimulatory cells. We propose that induced cell death of active effector T cells provides a third mechanism of tolerance in addition to intrathymic deletion of developing autoreactive T cells and peripheral inactivation of mature, naive T cells.