The study of lymphokines has been almost entirely conducted by utilizing in vitro assay systems, long term cell lines, and clones. Thus, little information is available concerning the production of lymphokines/cytokines in vivo after specific antigenic stimulation. In order to address this limitation, we have modified the mRNA phenotyping system to allow for the quantitation of lymphokine mRNA after antigenic stimulation in vivo. We report here the production of both IL-2 and IL-4 mRNA in vivo after primary sensitization with picryl chloride. However, the time course of IL-2 and IL-4 mRNA production is discordant. The majority of IL-2 mRNA expression occurs from 1 to 3 days after antigenic exposure, whereas IL-4 mRNA expression occurs mainly from day 3 through day 5. Thus, the production in vivo of these two lymphokine mRNA after sensitization with picryl chloride appears to occur as a "cascade." These results 1) demonstrate that IL-4 mRNA is induced during a primary immune response in vivo and 2) raise the possibility that the generation of an immune response in vivo may involve a specific sequential production of certain lymphokines.