Using an in vitro model for the development of IFN-gamma-producing (Th1) and IL-4-producing (Th2) cells from CD4+ T lymphocytes expressing a transgenic TCR, we show that IL-12 and IL-4 are the most potent stimuli for the differentiation of naive T cells to effector populations. When combinations of cytokines are present during T cell priming, the effect of IL-4 is dominant. Furthermore, differentiated Th1 cells can be converted into IL-4 producers by exposure to IL-4, but the Th2 phenotype is not reversible. The stability of Th2 populations may limit the ability to regulate Th2-dominant responses in pathologic situations.