IL-12 mediated activation of human MHC-unrestricted cytotoxicity was studied with freshly isolated, highly enriched CD56 +CD3- NK cells (95.98%), monocytes/macrophages (90-95%) and CD3 + T cells (95-98%). Activation of NK cell cytotoxicity and monocyte cytotoxicity by IL-12 were independent of exogenous IL-2 and IFN gamma. Activation of CD3+T cells to MHC-unrestricted cytotoxicity required coactivation by anti-CD3 antibody. The enhanced cytotoxicities were directed against NK-sensitive as well as NK-resistant target cells and coincided with enhancement of effector cell/target cell conjugate formation. The specific cytotoxicity of all three activated effector cell populations was further increased in the presence of rhamnogalacturonan. These increases were based on an additional increase of effector cell/target cell conjugate formation that is based on rhamnogalacturonan-mediated bridging between effector cells and target cells. Simultaneous enhancement of cytotoxicity indicates involvement of receptors on effector cells cross-reacting with acetylrhamnose (6-deoxymannose) that might play an important role in human MHC-unrestricted cytotoxicity against tumor cells.