Ag-induced, CD4 T cell-dependent synthesis of IL-4 and IFN-gamma plays a critical role in the induction, maintenance, and regulation of allergic responses. The requirement for IL-2 and IL-4 in the initial induction of IL-4 T cell responses is well established. However, it remains unclear whether IL-2 is required for priming of IL-4 responses, IL-4 gene expression, or both. In this report, we dissociate the IL-2 dependence of developing and established IL-4 responses. The capacity of spleen cells from naive and allergen-immunized mice to synthesize IL-4 after Ag-specific vs polyclonal restimulation is examined in overnight cultures. Although de novo induction of IL-4 and IFN-gamma production obtained after in vitro activation of cells from naive animals with immobilized anti-CD3 is IL-2 dependent, Ag-driven IL-4 synthesis by CD4 T cells from OVA (alum)- or ragweed extract (alum)-immunized mice is independent of IL-2. The data demonstrate the IL-2 independence of CD4 T cell-derived IL-4 synthesis by allergen-primed cells, distinguishing IL-2-dependent from IL-2-independent stages of IL-4 responses. In contrast to the finding that IL-2 is not required for IL-4 gene expression by primed T cells in allergen-driven responses, both induction and expression of IFN-gamma responses are strictly IL-2 dependent. This differential requirement for IL-2 in IL-4 and IFN-gamma gene expression may be significant in the maintenance of IL-4-dominated responses in allergic individuals.