IL-4 is important in controlling the development of immune responses. Following activation with anti-CD3e under serum-free conditions, splenocytes from most normal (neu-7') mouse strains directly produced IL-4 and other T cell cytokines. However, splenic T cells from SM/J and B1O.SM (H-21; neu-1") strain mice, deficient in neu-7 sialidase activity, failed to produce IL-4 but produced normal levels of IL-2 following activation. Moreover, sialidase-deficient mice produced markedly less IgE and lgGl Abs following immunization with protein Ags than did mouse strains with normal neu-7 sialidase activity. Enriched T cells from newla mice failed to be effectively primed with exogenous murine 11-4 to become IL-4-producing cells. Treatment of splenocytes or enriched T cells from neu-V mice with bacterial sialidase prior to activation or IL-4 priming promoted their subsequent capacity to produce IL-4. In contrast, activation of T cells from neu-7' mice in the presence of a sialidase inhibitor almost completely blocked subsequent IL-4 production. The presence of IL-4 during priming enhanced T cell expression of neu-7-specific sialidase activity and increased the membrane expression of asialo-G,, compared with T cells activated without 1L-4. These results suggest that T cell-associated neu-1 sialidase is required for early IL-4 production by splenic T cells and is involved in the 11-4 priming process of conventional T cells to become active IL-4 producers.