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Skin is an immunological organ consisting of epidermal cells, i.e. keratinocytes and Langerhans cells (LCs, antigen-presenting dendritic cells), and both innate and acquired immune systems operate upon exposure of the skin to various external microbes or their elements. To explore the relationship between innate and acquired immunities in the skin, we investigated whether Toll-like receptor (TLR) ligation of epidermal cells enhances the ability of LCs to present a specific antigen to T cells in mice. LC-containing epidermal cells were incubated with CpG oligonucleotide (TLR9 ligand) modified with trinitrophenyl hapten, and cultured with hapten-primed CD4+ T cells. TLR9 ligand was capable of enhancing the hapten-presenting ability of LCs when LC-enriched epidermal cells, but not purified LCs, were used as the LC source, suggesting that bystander keratinocytes play a role in the enhancement of LC function. Cultivation of freshly isolated epidermal cells with CpG promoted the expression of major histocompatibility complex (MHC) class II and CD86 molecules on LCs. CpG enhanced the production of interleukin (IL)-1α, granulocyte–macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor (TNF)-α by primarily cultured keratinocytes. The addition of a cocktail of neutralizing antibodies against these cytokines abrogated the CpG-promoted, antigen-presenting ability of LC-enriched epidermal cells. Moreover, the addition of culture supernatants from CpG-stimulated keratinocytes restored the ability of purified LCs. Our study demonstrated that although the direct effect of CpG on LCs is minimal, LC function can be up-regulated indirectly by cytokines released by CpG-stimulated keratinocytes. This also implies that innate immunity evoked by TLR ligation of keratinocytes enhances acquired immunity comprising LCs and T cells.