We recently reported that human epidermal Langerhans cells (LCs) are more efficient than dermal CD14⁺ DCs at priming naive CD8⁺ T cells into potent CTLs. We hypothesized that distinctive dendritic cell (DC) cytokine expression profiles (ie, IL-15 produced by LCs and IL-10 expressed by dermal CD14⁺ DCs) might explain the observed functional difference. Blocking IL-15 during CD8⁺ T-cell priming reduced T-cell proliferation by ∼ 50%. These IL-15–deprived CD8⁺ T cells did not acquire the phenotype of effector memory cells. They secreted less IL-2 and IFN-γ and expressed only low amounts of CD107a, granzymes and perforin, and reduced levels of the antiapoptotic protein Bcl-2. Confocal microscopy analysis showed that IL-15 is localized at the immunologic synapse of LCs and naive CD8⁺ T cells. Conversely, blocking IL-10 during cocultures of dermal CD14⁺ DCs and naive CD8⁺ T cells enhanced the generation of effector CTLs, whereas addition of IL-10 to cultures of LCs and naive CD8⁺ T cells inhibited their induction. TGF-β1 that is transcribed by dermal CD14⁺ DCs further enhanced the inhibitory effect of IL-10. Thus, the respective production of IL-15 and IL-10 explains the contrasting effects of LCs and dermal CD14⁺ DCs on CD8⁺ T-cell priming.