The antimurine CD2 mAb 12-15 was administered intravenously to investigate the role of CD2 in cell-mediated immunity in vivo. The anti-CD2 mAb was able to diminish the contact sensitivity response to the hapten trinitrophenyl and was most effective when administered during the efferent or elicitative phase of immunity. Antibody treatment was also able to inhibit in vivo priming for subsequent generation of secondary, TNP-specific CTL in vitro. This inhibitory effect was most effective in the afferent or early phase of immunity. Indeed antibody could be injected at least 3 weeks prior to in vivo antigen priming, and the subsequent CTL response was still suppressed. Additional experiments showed a well-defined dose-response relationship between the amount of anti-CD2 administered and subsequent immunosuppression. Control experiments showed that other isotype-matched antibodies were not suppressive and that the anti-CD2 was not merely shifting the kinetics of the CTL response. Further experiments revealed that in vivo mAb treatment could also inhibit the subsequent development of primary, alloantigen-specific CTL in vitro while the mixed lymphocyte reaction (MLR) remained unchanged. FACS analysis revealed a marked downmodulation of CD2 in vivo, a small and variable decrease in CD8, and essentially no change in CD3 or CD4 after treatment with anti-CD2. The F(ab')2 fragment was not able to downmodulate CD2 or to suppress CTL activity at the doses tested. These results support a major role for CD2 in diverse aspects of cell-mediated immunity affecting both CD4+ and CD8+ effector T cells. The anti-CD2 mAb functions not by deleting or depleting relevant cell populations but rather by altering the array of cell surface receptors and subsequent responses to antigenic challenge.