Induction of Th1-biased cytokine production by {alpha}-carba-GalCer, a neoglycolipid ligand for NKT cells

T Tashiro, E Sekine Kondo, T Shigeura, R Nakagawa, S Inoue, M Omori Miyake, T Chiba, N Hongo, S. i Fujii, K Shimizu, Y Yoshiga, T Sumida, K Mori, H Watarai and M. Taniguchi

International Immunology, 2010, 22(4), 319-328. DOI: 10.1093/intimm/dxq012

Abstract

NKT cells are characterized by their production of both Th1 and Th2 cytokines immediately after stimulation with -galactosylceramide (-GalCer), which is composed of -galactopyranose linked to ceramide (itself composed of sphingosine and fatty-acyl chains); the chain length of the ceramide varies and this affects the ability of -GalCer to stimulate cytokine production. However, the contribution of its galactopyranose sugar moiety remains unclear. We synthesized -carba-GalCer, which has an -linked carba-galactosyl moiety; here, the 5a'-oxygen atom of the D-galactopyranose ring of -GalCer is replaced by a methylene group. The -carba-GalCer was more stable and showed higher affinity to the NKT receptor. It thus enhanced and prolonged production of IL-12 and IFN- compared with -GalCer, resulting in augmented NKT cell-mediated adjuvant effects in vivo. The -carba-GalCer, which has an ether linkage, was more resistant to degradation by liver microsomes than was -GalCer, which has an acetal bond. Modulation of the sugar moiety in glycolipids might therefore provide optimal therapeutic reagents for protective immune responses against tumor or pathogens.

ASCI-ID: 1087-123