Dendritic cells (DC) are unmatched among APCs in their ability to bind, process, and present Ag. Presentation by such potent APCs, if always immunogenic and never tolerogenic, might stimulate pathogenic autoimmune responses. To determine whether Ag presentation by DC can induce tolerance, mice were injected with a rat IgG2b anti-splenic DC mAb, 33D1, and challenged 13 to 28 days later with a stimulatory rat IgG2b mAb. Injection of mice with 1 ng/100 micrograms of 33D1 rarely induced an anti-rat IgG2b Ab response and, in most mice, induced rat IgG2b-specific T cell and B cell tolerance. Tolerant mice had decreased ability to secrete Ab and make both type 1 and type 2 cytokine mRNA and protein in response to immunization with rat IgG2b. 33D1 was 100- to 1000-fold more potent as a tolerogen than an isotype-matched control rat IgG2b mAb. Injecting mice with aggregated 33D1, 33D1 plus anti-IgD mAb, or 33D1 plus IL-1 induced an IgG1 anti-rat IgG2b Ab response rather than tolerance. IL-1 injected 3 days after 33D1 still induced an Ab response rather than tolerance. Not all anti-DC mAbs are tolerogenic. Injection of a DC-specific hamster anti-CD11c mAb (N418) stimulates an IgG anti-hamster response, and injection of 33D1 plus N418 stimulates both anti-hamster and anti-rat IgG2b responses. These observations indicate that DCs can present Ag in either a tolerogenic or stimulatory manner and suggest that inflammatory stimuli can convert an otherwise tolerogenic signal to a stimulatory signal.