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Vasoactive intestinal polypeptide (VIP) was found to be a potent stimulator of lymphocyte adenylate cyclase activity. VIP-induced activation of adenylate cyclase was specific for lymphocytes among peripheral blood cells; i.e., VIP did not stimulate the adenylate cyclase activity of neutrophils, monocytes, or platelets. The VIP-induced activation of lymphocyte adenylate cyclase was time, temperature, and concentration dependent. VIP and the GTP analog, Gpp(NH)p, acted synergistically to stimulate lymphocyte adenylate cyclase; stimulation by VIP and PGE1 was additive; and VIP activation was antagonized by somatostatin. VIP-mediated activation of lymphocyte adenylate cyclase was observed in normal human T cells, B cells obtained from a patient with chronic lymphocytic leukemia, and a human T cell culture line. The Raji human B cell culture line did possess adenylate cyclase activity, but this activity was …