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

• Published in: International immunology 2010-04, Vol.22 (4), p.319-328
• Main Authors: Tashiro, Takuya, Sekine-Kondo, Etsuko, Shigeura, Tomokuni, Nakagawa, Ryusuke, Inoue, Sayo, Omori-Miyake, Miyuki, Chiba, Tomoki, Hongo, Naomi, Fujii, Shin-ichiro, Shimizu, Kanako, Yoshiga, Yohei, Sumida, Takayuki, Mori, Kenji, Watarai, Hiroshi, Taniguchi, Masaru
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - chemical synthesis; Adjuvants, Immunologic - chemistry; Adjuvants, Immunologic - pharmacology; Animals; CD1d; Cell Line; Cyclohexanols - chemical synthesis; Cyclohexanols - chemistry; Cyclohexanols - pharmacology; Cytokines - analysis; Cytokines - biosynthesis; Galactosylceramides - chemical synthesis; Galactosylceramides - chemistry; Galactosylceramides - pharmacology; glycolipid; Glycolipids - metabolism; Humans; IFN-γ; Injections, Intravenous; Ligands; Mice; Natural Killer T-Cells - drug effects; Natural Killer T-Cells - immunology; NKT cells; TCR; Th1 Cells - immunology
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxq012

NKT cells are characterized by their production of both Th1 and Th2 cytokines immediately after stimulation with α-galactosylceramide (α-GalCer), which is composed of α-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 α-GalCer to stimulate cytokine production. However, the contribution of its galactopyranose sugar moiety remains unclear. We synthesized α-carba-GalCer, which has an α-linked carba-galactosyl moiety; here, the 5a′-oxygen atom of the D-galactopyranose ring of α-GalCer is replaced by a methylene group. The α-carba-GalCer was more stable and showed higher affinity to the NKT receptor. It thus enhanced and prolonged production of IL-12 and IFN-γ compared with α-GalCer, resulting in augmented NKT cell-mediated adjuvant effects in vivo. The α-carba-GalCer, which has an ether linkage, was more resistant to degradation by liver microsomes than was α-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.