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.

CONCLUSION:

α-GalCer significantly suppressed GPI peptide-induced arthritis through the suppression of GPI-specific CD4+ T cells.

• Authors: Masanobu Horikoshi, Daisuke Goto, Seiji Segawa, Yohei Yoshiga, Keiichi Iwanami, Asuka Inoue, Yuki Tanaka, Isao Matsumoto, Takayuki Sumida
• Journal: PloS one (PLoS One) Vol. 7 Issue 12 Pg. e51215 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23251456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Galactosylceramides
• Glycolipids
• Ligands
• alpha-galactosylceramide
• Glucose-6-Phosphate Isomerase

Topics

• Animals
• Arthritis (enzymology, etiology, metabolism)
• CD4-Positive T-Lymphocytes (metabolism)
• Cytokines (blood)
• Galactosylceramides (metabolism)
• Glucose-6-Phosphate Isomerase (metabolism)
• Glycolipids (metabolism)
• Killer Cells, Natural (immunology)
• Ligands
• Lymphocyte Activation
• Male
• Mice
• Mice, Inbred DBA