Stimulation of previously activated T cells through the antigen receptor can result in the apoptotic death of the responding cell, a process referred to as activation-induced cell death (AICD). This process appears to involve Fas (CD95) and tts ligand (Fas-L). The distribution of Fas and Fas-L on various T cell subsets has not been extensively characterized. We have therefore analyzed cells committed to a T_h1- or T_h2-type differentiation pattern for the expression and function of Fas-L. Using both a sensitive bloassay and flow cytometry, we demonstrate that cloned T_h1 cells express high levels of Fas-L, whereas cloned T_h cells express only low levels. The expression of Fas-L by T_h1 and T_h2 cells correlates with the relative abilities of these two cell types to undergo AICD. Whereas AICD is readily observed in cultures of cloned T_h1, but not T_h2 cells, T_h2 cells are capable of undergoing apoptosls in the presence of T_h1 cells expressing Fas-L The ability of T cells to undergo AICD appears to be unrelated to the presence of various cytokines. Thus, the Fas/Fas-L pathway appears to be critical for the induction of AICD and this pathway is differentially regulated in cells committed to either T_h1 or T_h2 differentiation.