Bacterial DNA and CpG-containing oligodeoxynucleotides activate cutaneous dendritic cells and induce IL-12 production: Implications for the augmentation of Th1 responses

Background: Unmethylated CpG sequences in bacterial DNA act as adjuvants se lectively inducing Th1 predominant immune responses during genetic vaccinat ion or when used in conjunction with protein Ag. The precise mechanism of t his adjuvant effect is unknown. Because dendritic cells (DC) are thought to be crucially involved in T cell priming and Th1/Th2 education during vacci nation via skin, we characterized the effects of bacterial DNA and CpG-cont aining oligodeoxynucleotides (CpG ODN) on cutaneous DC. Methods and Results: Stimulation with CpG ODN 1826 (6 mu g/ml) induced acti vation of immature Langerhans cell (LC)-like DC as determined by an increas ed expression of MHC class II and costimulatory molecules, loss of E-cadher in-mediated adhesion and increased ability to stimulate allogeneic T cells. Composition-matched control ODN 1911 lacking CpG sequences at equal concen trations was without effect. In comparison to LPS and ODN 1911, CpG ODN 182 6 selectively stimulated DC to release large amounts of IL-12 (p40) and lit tle IL-6 or TNF-alpha within 18 h and detectable levels of IL-12 p70 within 72 h. Stimulation with Escherichia coli DNA, but not calf thymus DNA, simi larly induced DC maturation and IL-12 p40 production. Injection of CpG ODN into murine dermis induced enhanced expression of MHC class II and CD86 by LC in the overlying epidermis and intracytoplasmic IL-12 p40 accumulation i n a subpopulation of activated LC. Conclusion: Bacterial DNA and CpG ODN stimulate DC in vitro and in vivo and may preferentially elicit Th1-predominant immune responses because they ca n activate and mobilize DC, inducing them to produce IL-12.