Preferential Induction of IL-4 Is Determined by the Type and Duration of Antigenic Stimulation

The transition of lymphokine production from IL-2 to IL-4 was investigated with antigen-primed lymph node cells (LNC) by observing cytokine release following sequential cycles of antigen exposure in vitro. LNC from mice infected with Nipponstrongylus brasiliensis (Nb), Trichinella spiralis, or primed with giant ragweed pollen demonstrated a pattern of dominant IL-2 production at 24 hr; however, there was a switch to predominantly IL-4 production within 72 hr following the first cycle of in vitro antigenic stimulation. In addition, repeated antigenic stimulation with these antigens shifted the pattern to IL-4 production. In contrast, only IL-2 production was observed after a single cycle of in vitro antigenic challenge with haptens (e.g., NP-O-succinimide or trimethylammonium hapten) or the naive allogenic spleen cells. Thereafter, the lymphokine production pattern gradually changed from IL-2 alone to mixtures of IL-2 and IL-4, and finally to predominant IL-4 secretion. In contrast, following priming with purified protein derivatives (PPD), it was difficult to detect IL-4 release even after nine successive weekly stimulations. However, activation of PPD-primed cells with anti-CD3 antibody resulted in IL-4 secretion. Furthermore, Nb-primed T cells, which produced IL-4 alone after repeated antigenic stimulation, produced IL-2 when stimulated in the presence of cycloheximide. These results suggest that (1) immune populations regulate cytokine production, (2) the IL-2/IL-4 profile is dependent on the type and duration of antigenic stimulation, and (3) production or accumulation of cycloheximide-sensitive proteins is critical for the switch from IL-2 to IL-4 secretion.