IL-18 directs autoreactive T cells and promotes autodestruction in the central nervous system via induction of IFN-gamma by NK cells.
IL-18 promotes NK cell and Th1 cell activity and may bridge innate and adaptive immune responses. Myelin oligodendrocyte glycoprotein (MOG) is a myelin component of the CNS and is a candidate autoantigen in multiple sclerosis. In the present study we show that IL-18-deficient (IL-18-/-) mice are defective in mounting autoreactive Th1 and autoantibody responses and are resistant to MOG35-55 peptide-induced autoimmune encephalomyelitis. IL-18 administration enhances the disease severity in wild-type mice and restores the ability to generate Th1 response in the IL-18-/- mice. This restoration was abrogated in NK cell-depleted mice, indicating that the action of IL-18 in promoting the generation of MOG-specific Th cells was dependent on NK cells. Furthermore, transfer of NK cells from recombinase-activating gene 1-/- mice, but not from recombinase-activating gene 1/IFN-gamma-/- mice, rescued the defective Th1 responses in IL-18-/- mice and rendered IL-18-/- mice susceptible to the induction of autoimmune encephalomyelitis. Thus, IL-18 can direct autoreactive T cells and promote autodestruction in the CNS at least in part via induction of IFN-gamma by NK cells.
Shi
F D
FD
Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden. fdshi@scripps.edu
Takeda
K
K
Akira
S
S
Sarvetnick
N
N
Ljunggren
H G
HG
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000502:physiology; D020382:Interleukin-18 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D001323:Autoantibodies; D001324:Autoantigens; D020382:Interleukin-18; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D007371:Interferon-gamma