A single early activation of invariant NK T cells confers long-term protection against collagen-induced arthritis in a ligand-specific manner.
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.
Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Ghent University Hospital, Ghent University, Ghent, Belgium.
Ken
K
Coppieters
Katrien
K
Van Beneden
Peggy
P
Jacques
Pieter
P
Dewint
Ann
A
Vervloet
Bert
B
Vander Cruyssen
Serge
S
Van Calenbergh
Guangwu
G
Chen
Richard W
RW
Franck
Gust
G
Verbruggen
Dieter
D
Deforce
Patrick
P
Matthys
Moriya
M
Tsuji
Pieter
P
Rottiers
Dirk
D
Elewaut
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000473:pathology; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D017252:CD3 Complex / Q000276:immunology; D005699:Galactosylceramides / Q000008:administration & dosage*; D007155:Immunologic Factors / Q000008:administration & dosage*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D013997:Time Factors
D017252:CD3 Complex; D005699:Galactosylceramides; D007155:Immunologic Factors; D008024:Ligands; C493154:alpha-galactosylceramide; D016753:Interleukin-10; D007371:Interferon-gamma