title: Preferential T(h)2 polarization by OCH is supported by incompetent NKT cell induction of CD40L and following production of inflammatory cytokines by bystander cells in vivo.
abstract: The altered glycolipid ligand OCH is a selective inducer of T(h)2 cytokines from NKT cells and a potent therapeutic reagent for T(h)1-mediated autoimmune diseases. Although we have previously shown the intrinsic molecular mechanism of preferential IL-4 production by OCH-stimulated NKT cells, little is known about the extrinsic regulatory network for IFN-gamma production. Here we demonstrate that OCH induces lower production of IFN-gamma, not only by NKT cells but also by NK cells compared with alpha-galactosylceramide. OCH induced lower IL-12 production due to ineffective primary IFN-gamma and CD40 ligand expression by NKT cells, and resulted in lower secondary IFN-gamma induction. Co-injection of a sub-optimal dose of IFN-gamma and stimulatory anti-CD40 mAb compensates for the lower induction of IL-12 by OCH administration. IL-12 converts OCH-induced cytokine expression from IL-4 predominance to IFN-gamma predominance. Furthermore, CpG oligodeoxynucleotide augmented IL-12 production when co-administrated with OCH, resulting in increased IFN-gamma production. Taken together, the lower IL-12 production and subsequent lack of secondary IFN-gamma burst support the effective T(h)2 polarization of T cells by OCH. In addition, highlighted in this study is the characteristic property of OCH that can induce the differential production of IFN-gamma or IL-4 according to the availability of IL-12.
authors.affiliation: Department of Immunology, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Oki
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tomi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamura
authors.forename: Sachiko
authors.initials: S
authors.lastname: Miyake
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology; D024201:Bystander Effect / Q000187:drug effects / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D006017:Glycolipids / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D006017:Glycolipids; C501055:tetracosanoic acid 1-galactopyranosyloxy-3,4-dihydroxydec-2-yl amide; D023201:CD40 Ligand