title: Induction of Th1-biased cytokine production by alpha-carba-GalCer, a neoglycolipid ligand for NKT cells.
abstract: NKT cells are characterized by their production of both T(h)1 and T(h)2 cytokines immediately after stimulation with alpha-galactosylceramide (alpha-GalCer), which is composed of alpha-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 alpha-GalCer to stimulate cytokine production. However, the contribution of its galactopyranose sugar moiety remains unclear. We synthesized alpha-carba-GalCer, which has an alpha-linked carba-galactosyl moiety; here, the 5a'-oxygen atom of the D-galactopyranose ring of alpha-GalCer is replaced by a methylene group. The alpha-carba-GalCer was more stable and showed higher affinity to the NKT receptor. It thus enhanced and prolonged production of IL-12 and IFN-gamma compared with alpha-GalCer, resulting in augmented NKT cell-mediated adjuvant effects in vivo. The alpha-carba-GalCer, which has an ether linkage, was more resistant to degradation by liver microsomes than was alpha-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.
authors.affiliation: Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Tsurumi, Yokohama, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Tashiro
authors.forename: Etsuko
authors.initials: E
authors.lastname: Sekine-Kondo
authors.forename: Tomokuni
authors.initials: T
authors.lastname: Shigeura
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Nakagawa
authors.forename: Sayo
authors.initials: S
authors.lastname: Inoue
authors.forename: Miyuki
authors.initials: M
authors.lastname: Omori-Miyake
authors.forename: Tomoki
authors.initials: T
authors.lastname: Chiba
authors.forename: Naomi
authors.initials: N
authors.lastname: Hongo
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Fujii
authors.forename: Kanako
authors.initials: K
authors.lastname: Shimizu
authors.forename: Yohei
authors.initials: Y
authors.lastname: Yoshiga
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
authors.forename: Kenji
authors.initials: K
authors.lastname: Mori
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watarai
authors.forename: Masaru
authors.initials: M
authors.lastname: Taniguchi
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D003511:Cyclohexanols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis*; D005699:Galactosylceramides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006017:Glycolipids / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D008024:Ligands; D051379:Mice; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D003511:Cyclohexanols; D016207:Cytokines; D005699:Galactosylceramides; D006017:Glycolipids; D008024:Ligands