title: Activation of Invariant NKT cells with glycolipid ligand α-galactosylceramide ameliorates glucose-6-phosphate isomerase peptide-induced arthritis.
abstract: OBJECTIVE
  Invariant natural killer T (iNKT) cells regulate collagen-induced arthritis (CIA) when activated by their potent glycolipid ligand, alpha-galactosylceramide (α-GalCer). Glucose-6-phosphate isomerase (GPI)-induced arthritis is a closer model of human rheumatoid arthritis based on its association with CD4+ T cells and cytokines such as TNF-α and IL-6 than CIA. Dominant T cell epitope peptide of GPI (GPI325-339) can induce arthritis similar to GPI-induced arthritis. In this study, we investigated the roles of activation of iNKT cells by α-GalCer in GPI peptide-induced arthritis.
  
  
  METHODS
  Arthritis was induced in susceptible DBA1 mice with GPI peptide and its severity was assessed clinically. The arthritic mice were treated with either the vehicle (DMSO) or α-GalCer. iNKT cells were detected in draining lymph nodes (dLNs) by flow cytometry, while serum anti-GPI antibody levels were measured by enzyme-linked immunosorbent assay. To evaluate GPI peptide-specific cytokine production from CD4+ T cells, immunized mice were euthanized and dLN CD4+ cells were re-stimulated by GPI-peptide in the presence of antigen-presenting cells.
  
  
  RESULTS
  α-GalCer induced iNKT cell expansion in dLNs and significantly decreased the severity of GPI peptide-induced arthritis. In α-GalCer-treated mice, anti-GPI antibody production (total IgG, IgG1, IgG2b) and IL-17, IFN-γ, IL-2, and TNF-α produced by GPI peptide-specific T cells were significantly suppressed at day 10. Moreover, GPI-reactive T cells from mice immunized with GPI and α-GalCer did not generate any cytokines even when these cells were co-cultured with APC from mice immunized with GPI alone. In vitro depletion of iNKT cells did not alter the suppressive effect of α-GalCer on CD4+ T cells.
  
  
  CONCLUSIONS
  α-GalCer significantly suppressed GPI peptide-induced arthritis through the suppression of GPI-specific CD4+ T cells.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Horikoshi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Goto
authors.forename: Seiji
authors.initials: S
authors.lastname: Segawa
authors.forename: Yohei
authors.initials: Y
authors.lastname: Yoshiga
authors.forename: Keiichi
authors.initials: K
authors.lastname: Iwanami
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
mesh_terms: D000818:Animals; D001168:Arthritis / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D005699:Galactosylceramides / Q000378:metabolism*; D005956:Glucose-6-Phosphate Isomerase / Q000378:metabolism*; D006017:Glycolipids / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA
chemical_list: D016207:Cytokines; D005699:Galactosylceramides; D006017:Glycolipids; D008024:Ligands; C493154:alpha-galactosylceramide; D005956:Glucose-6-Phosphate Isomerase