Activation of human invariant natural killer T cells with a thioglycoside analogue of α-galactosylceramide

Activation of CD1d-restricted invariant NKT (iNKT) cells with the glycolipid alpha-galactosylceramide (alpha-GalCer) confers protection against disease in murine models, however, clinical trials in humans have had limited impact. We synthesized a novel thioglycoside analogue of alpha-GalCer, denoted alpha-S-GalCer, and tested its efficacy for stimulating human iNKT cells in vitro. alpha-S-GalCer stimulated cytokine release by iNKT cells in a CD1d-dependent manner and primed CD1d(+) target cells for lysis. alpha-S-GalCer-stimulated iNKT cells induced maturation of monocyte-derived dendritic cells into antigen-presenting cells that released IL-12 and small amounts of IL-10. The nature and potency of alpha-S-GalCer and alpha-GalCer in human iNKT cell activation were similar. However, in contrast to alpha-GalCer, alpha-S-GalCer did not activate murine iNKT cells in vivo. Because of its enhanced stability in biological systems, alpha-S-GalCer may be superior to alpha-GalCer as a parent compound for developing adjuvant therapies for humans. (C) 2011 Elsevier Inc. All rights reserved.