CGRP is a 37-amino acid neuropeptide found in the central and peripheral nervous systems as well as the nerve endings in lymphoid organs. Specific CGRP receptors are present on both T and B lymphocytes. There is increasing evidence that CGRP plays a role in regulation of the immune response. However, few investigations have examined the effects of CGRP on lymphocyte effector functions. In this report, CGRP (0.1 nM-1 microM) was shown to cause concentration-dependent inhibition of IL-2-activated lymphocyte growth inhibition of the fungus Candida albicans and cytotoxic activity for tumor cells. Maximum inhibition of lymphocyte activity by CGRP was 47.4% for the hyphae of C. albicans, 44.8% for a natural killer cell susceptible cell line, and 52.9% for a natural killer cell-resistant cell line. CGRP-mediated inhibition of lymphocyte function was mimicked by 8-bromo-cAMP (1 mM) and was correlated in a concentration-dependent manner with an increase in intracellular levels of cAMP. These increases were potentiated by pretreatment of the lymphocytes with 3-isobutyl-1-methylxanthine (0.5 mM, 10 min), an inhibitor of the cAMP phosphodiesterase. hCGRP 8-37, a selective blocker of the CGRP1 receptor, abrogated the effect of CGRP on lymphocyte function and on intracellular cAMP level elevation induced by rCGRP. CGRP had no direct effect on the capacity of IL-2-activated lymphocytes to adhere to the hyphae of C. albicans. However, both CGRP and 8-bromo-cAMP diminished the capacity of the lymphocytes to release cytoplasmic granular content when stimulated by the hyphae of C. albicans. These data show that CGRP inhibits functional activity of IL-2-activated lymphocytes and suggest that hCGRP8-37 may be a useful tool for assessing the role of CGRP in the immune system.