The neuropeptide vasoactive intestinal peptide (VIP) has been previously reported to inhibit T cell proliferation. Here we report on the effect of VIP on IL-2 and on IFN gamma production by murine T lymphocytes stimulated with mitogens (ConA), or activated through the antigen-specific T cell receptor. VIP inhibited IL-2 production by either unfractionated spleen cells, or by purified CD4+ T cells in a dose-dependent manner. The effect was specific, since structurally related peptides such as secretin and glucagon had little or no inhibitory effect. VIP induced a rapid increase in intracellular cAMP in CD4+ T cells, suggesting that the inhibitory effect of VIP could be mediated through the induction of cAMP. Northern blots showed that VIP downregulated IL-2 mRNA, indicating the occurrence of a transcriptional regulatory event. In contrast with its effect on IL-2, VIP did not affect IFN gamma production by either mitogen-stimulated normal T lymphocytes, or by the L12R4 murine T cell line which produces IFN gamma in response to PMA stimulation.