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A Single Early Activation of Invariant NK T Cells Confers Long-Term Protection against Collagen-Induced Arthritis in a Ligand-Specific Manner1

The glycosphingolipid α-galactosylceramide (α-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 α-GalCer (α-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 α-GalCer when administered early rather than late during the disease. Surprisingly, the Th1-polarizing analog α-C-GalCer also conferred protection. Furthermore, a biphasic role of IFN-γ in the effect of iNKT cell stimulation was observed. Whereas in vivo neutralization of IFN-γ release induced by either α-GalCer or α-C-GalCer early during the course of disease resulted in partial improvement of clinical arthritis symptoms, blockade of IFN-γ 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 α-GalCer-treated mice produced significantly higher amounts of IL-10 upon systemic anti-CD3 stimulation compared with PBS controls, T cells from α-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-γ-dependent immunomodulatory effects of iNKT cells in collagen-induced arthritis.