Administration of α-galactosylceramide impairs the survival of dendritic cell subpopulations in vivo

In this study, we examine whether recognition of α-Gal-Cer presented on CD1d-expressing DCs and B cells in ivo elicits the cytotoxic activity of iNKT cells and elimination of α-GalCer-presenting cells. We report that i.v. injection of α-GalCer induced a decrease in the percentage and number of splenic CD8⁺Langerin⁺ DCs, while CD8^- DCs were not affected. The decline in CD8⁺ DC numbers was clearly detectable by 15 h after α-Gal- Cer injection, was maximal at 24-48 h, returned to normal by day 7, and was accompanied by a reduced cross-presentation of OVA protein given i.v. to specific CD8⁺ T cells in vitro. The decrease in the numbers of CD8⁺ DCs required iNKT cells but was independent of perforin, Fas, or IFN-γ, as it was observed in mice deficient in each of these molecules. In contrast, treatment with a TNF-α-neutralizing antibody was effective at reducing the decline in CD8⁺ DC numbers and DC activation. Treatment with immunostimulatory CpG ODN also resulted in DC activation and a decreased number of CD8⁺ DCs; however, the decline in DC number was a result of down-regulation of CD11c and CD8 and did not require iNKT cells or TNF- α. Although CD8⁺Langerin⁺ DCs appeared to be selectively affected by α-GalCer treatment, they were not required for early iNKT cell responses, as their prior depletion did not prevent the increase in serum TNF-α and IL-4 observed after α-Gal- Cer treatment. Thus, iNKT cells regulate the survival of CD8⁺ DCs through a mechanism that does not appear to involve direct cell killing.