The role of interleukin 4 (IL-4) (previously called B-cell stimulatory factor 1) in the response of T helper (TH) cells to antigen presented by antigen-specific B cells or splenic adherent cells was investigated. Antigenic stimulation of either a keyhole-limpet-hemocyanin-specific TH-cell line or two keyhole-limpet-hemocyanin-specific T-cell clones resulted in the secretion of IL-4 but not interleukin 2 (IL-2). The secretion of IL-4 was first detected in the culture supernatant 6-8 hr after antigenic stimulation. Induction of IL-4 secretion was antigen specific and major histocompatibility complex restricted. Antigenic stimulation also resulted in increased responsiveness of the TH cells to exogenously added or endogenously produced IL-4. The antigen-induced proliferation of the TH cells could be inhibited by an anti-IL-4 antibody but not by an anti-IL-2-receptor antibody. These results suggest that IL-4 mediates the proliferation of some TH cells by an antigen-induced autocrine mechanism. Taken together with past results, these data indicate that, during T-cell-B-cell interactions involving some soluble protein antigens, IL-4 and not IL-2 is the critical lymphokine for activating resting B cells and inducing proliferation of the TH cells.