alpha-Galactosylceramide (
alpha-GalCer) is the prototype compound for studying the presentation of
glycolipids on CD1d molecules to natural killer T (NKT) lymphocytes. A single i.v. dose of
glycolipid triggers a cascade of events involving the production of several
cytokines over the course of a day, a short-lived activation of NKT and natural killer (NK) cells, and a more prolonged adaptive T cell immune response if certain
antigens are given together with
alpha-GalCer. We find that a recently described analogue, alpha-
C-galactosylceramide (
alpha-C-GalCer), more potently induces these innate and adaptive immune responses in mice.
alpha-C-GalCer acts as a more effective trigger for
IL-12 and IFN-gamma production, although it minimally elicits
IL-4 and
TNF-alpha release into the serum. Also,
alpha-C-GalCer better mobilizes NKT and natural killer cells to resist
B16 melanoma. To help understand these effects, we find that
alpha-C-GalCer binds more stably to dendritic cells than
alpha-GalCer and that dendritic cells loaded with
alpha-C-GalCer induce larger and more long lasting NKT cell responses in vivo. When
glycolipid is targeted to dendritic cells in spleen together with
antigens in dying cells, such as irradiated
tumor cells,
alpha-C-GalCer is active as an adjuvant for T cell-mediated immunity at lower doses, just 20 ng per mouse, where it is also able to up-regulate the required
CD40L costimulatory molecule on NKT cells. Therefore,
alpha-C-GalCer represents a
glycolipid that binds more stably to dendritic cells and acts as a more effective link between innate and adaptive immunity in vivo.