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* Department of Immunology and
Advanced Medical Research Center, Toho University School of Medicine, Tokyo, Japan;
Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan; and
Department of Molecular Tumor Genetics and Immunogenetics, Max-Delbruck Center for Molecular Medicine, Berlin, Germany
CCL19 and CCL21 are thought to be critical for experimental autoimmune encephalomyelitis (EAE) induction, but their precise role is unknown. We examined the role of these chemokines in inducing EAE. C57BL/6 mice lacking expression of these chemokines (plt/plt mice) or their receptor CCR7 were resistant to EAE induced with myelin oligodendrocyte glycoprotein peptide 35–55 (MOG35–55) and pertussis toxin. However, passive transfer of pathogenic T cells from wild-type mice induced EAE in plt/plt mice, suggesting a defect independent of the role of CCR7 ligands in the migration of immune cells. Examination of draining lymph node (DLN) cells from MOG35–55-immunized plt/plt mice found decreased IL-23 and IL-12 production by plt/plt dendritic cells (DCs) and a concomitant defect in Th17 cell and Th1 cell generation. In contrast, production of the Th17 lineage commitment factors IL-6 and TGF-β were unaffected by loss of CCR7 ligands. The adoptive transfer of in vitro-generated Th17 cells from DLN cells of MOG35–55-immunized plt/plt mice developed EAE in wild-type recipient mice, whereas that of Th1 cells did not. Pathogenic Th17 cell generation was restored in plt/plt DLNs with the addition of exogenous IL-23 or CCL19/CCL21 and could be reversed by inclusion of anti-IL-23 mAb in cultures. Exogenous CCL19/CCL21 induced IL-23p19 expression and IL-23 production by plt/plt or wild-type DCs. Therefore, CCR7 ligands have a novel function in stimulating DCs to produce IL-23 and are important in the IL-23-dependent generation of pathogenic Th17 cells in EAE induction.
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1 This work was supported in part by Project Research of Toho University School of Medicine (to T.Ku., F.I., and Y.O.), the Research Promotion Grants from Toho University Graduate School of Medicine (Grant 05-02 to T.Ka., Grant 07-02 to T.Ku., and Grant 08-02 to Y.T.), and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science to T.Ka. (Grants 17590900 and 19591013), to T.Ku. (Grant 18790605), and to Y.K. (Grant 19790695).
2 Current address: Laboratory for Immunogenetics, RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan.
3 Current address: Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences. National Institutes of Health, 111 T.W. Alexander Drive, Building 101, E244, Research Triangle Park, NC 27709.
4 Address correspondence and reprint requests to Dr. Terutaka Kakiuchi, Department of Immunology, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo 143-8540, Japan. E-mail address: tkaki{at}med.toho-u.ac.jp
5 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; DC, dendritic cell; BMDC, bone marrow-derived DC; LN, lymph node; DLN, draining LN; MOG, myelin oligodendrocyte glycoprotein; rm, recombinant mouse; WT, wild type; PT, pertussis toxin.
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