Α-Lactosylceramide as a Novel “Sugar-Capped” CD1d Ligand for Natural Killer T Cells: Biased Cytokine Profile and Therapeutic Activities
2008
The invariant natural killer T cells (iNKT) cells have emerged as an important regulator of immunity to infection, cancer, and autoA diseases. They can be activated by glycolipids that bind to CD1d. The most effective iNKT ligand reported to date is a-galactosylceramide (a-GalCer), which stimulates iNKT cells to secrete both Th-1and Th-2 cytokines. Indiscriminate induction of both types of cytokines could limit the therapeutic potential of iNKT ligands, as Th-1and Th-2 cytokines play different roles under physiological and pathological conditions. Therefore, a ligand with a biased cytokine-release profile would be highly desirable. Here, we report the synthesis and biological activity of alactosylceramide (a-LacCer). Our data demonstrate that a-LacCer can stimulate iNKT cells to proliferate and release cytokines, both in vitro and in vivo. Interestingly, while a-LacCer is approximately 1000-times less efficient than a-GalCer in inducing Th-1cytokines, it is as potent as a-GalCer in the induction of Th-2 cytokines; therefore, a-LacCer is a novel compound that induces a biased cytokine release. Processing by b-glycosidase was critical for a-LacCer activity. Moreover, in vivo experiments suggest that a-LacCer is at least as potent as a-GalCer in the treatment of tumors and experimental autoimmune encephalomyelitis.
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