CpG ODN enhance antigen-specific NKT cell activation via plasmacytoid dendritic cells

Human Vα24+ Vβ11+ natural killer T cells (NKT cells) are “natural memory” T cells that detect glycolipid antigens such as α-galactosylceramide (α-GalCer) presented on CD1d. In the present study we found that highly purified Vα24+ NKT cells lack TLR9 mRNA, and thus are not sensitive towards stimulation with CpG oligodeoxynucleotides (ODN). Within PBMC, however, CpG ODN synergistically activated NKT cells stimulated with their cognate antigen α-GalCer. Depletion of plasmacytoid dendritic cells (PDC) or myeloid dendritic cells (MDC) revealed that both DC subsets were necessary for the synergistic activation of NKT cells by α-GalCer and CpG ODN. While PDC were responsible for the stimulation of NKT cells with CpG ODN, MDC but not PDC presented α-GalCer via CD1d. Partial activation of NKT cells was mediated by PDC-derived IFN-α, whereas full activation of NKT cells as indicated by IFN−γ production required cell-to-cell contact of PDC and NKT cells in addition to IFN-α; OX40 was involved in this interaction. We conclude that CpG-activated PDC enhance α-GalCer-specific NKT cell activation, and bias activated NKT cells towards a Th1 phenotype. Our results lead to a novel concept of PDC function: to regulate effector activity of antigen-stimulated T cells in a cell contact-dependent manner without the need of simultaneous presentation of the cognate T cell antigen.