A single early activation of invariant NK T cells confers long-term protection against collagen-induced arthritis in a ligand-specific manner.

Abstract

The glycosphingolipid alpha-galactosylceramide (alpha-GalCer) has been shown to be a potent activator of invariant NKT (iNKT) cells, rapidly inducing large amounts of both Th1 and Th2 cytokines upon injection in mice. The C-glycoside analog of alpha-GalCer (alpha-C-GalCer), by contrast, results in an enhanced Th1-type response upon activation of iNKT cells. We administered a single dose of these Ags to DBA/1 mice during the early induction phase of collagen-induced arthritis and demonstrated therapeutic efficacy of alpha-GalCer when administered early rather than late during the disease. Surprisingly, the Th1-polarizing analog alpha-C-GalCer also conferred protection. Furthermore, a biphasic role of IFN-gamma in the effect of iNKT cell stimulation was observed. Whereas in vivo neutralization of IFN-gamma release induced by either alpha-GalCer or alpha-C-GalCer early during the course of disease resulted in partial improvement of clinical arthritis symptoms, blockade of IFN-gamma release later on resulted in a more rapid onset of arthritis. Although no phenotypic changes in conventional T cells, macrophages, or APCs could be detected, important functional differences in T cell cytokine production in serum were observed upon polyclonal T cell activation, 2 wk after onset of arthritis. Whereas alpha-GalCer-treated mice produced significantly higher amounts of IL-10 upon systemic anti-CD3 stimulation compared with PBS controls, T cells from alpha-C-GalCer-treated mice, by contrast, produced substantially lower levels of cytokines, suggesting the involvement of different protective mechanisms. In conclusion, these findings suggest long-term, ligand-specific, time-dependent, and partially IFN-gamma-dependent immunomodulatory effects of iNKT cells in collagen-induced arthritis.

• Authors: Ken Coppieters, Katrien Van Beneden, Peggy Jacques, Pieter Dewint, Ann Vervloet, Bert Vander Cruyssen, Serge Van Calenbergh, Guangwu Chen, Richard W Franck, Gust Verbruggen, Dieter Deforce, Patrick Matthys, Moriya Tsuji, Pieter Rottiers, Dirk Elewaut
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 4 Pg. 2300-9 (Aug 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17675491 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD3 Complex
• Galactosylceramides
• Immunologic Factors
• Ligands
• alpha-galactosylceramide
• Interleukin-10
• Interferon-gamma

Topics

• Animals
• Antigen-Presenting Cells (immunology, pathology)
• Arthritis, Experimental (immunology, pathology, prevention & control)
• CD3 Complex (immunology)
• Galactosylceramides (administration & dosage)
• Immunologic Factors (administration & dosage)
• Interferon-gamma (immunology)
• Interleukin-10 (immunology)
• Killer Cells, Natural (immunology, pathology)
• Ligands
• Lymphocyte Activation (drug effects)
• Macrophages (immunology, pathology)
• Male
• Mice
• Mice, Inbred DBA
• Th1 Cells (immunology, pathology)
• Th2 Cells (immunology, pathology)
• Time Factors