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CCR 7 ligands are required for development of experimental autoimmune encephalomyelitis through generating IL-23-dependent Th17 cells

Item Type:Article
Title:CCR 7 ligands are required for development of experimental autoimmune encephalomyelitis through generating IL-23-dependent Th17 cells
Creators Name:Kuwabara, T. and Ishikawa, F. and Yasuda, T. and Aritomi, K. and Nakano, H. and Tanaka, Y. and Okada, Y. and Lipp, M. and Kakiuchi, T.
Abstract: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 (MOG(35-55)) 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 MOG(35-55)-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-beta were unaffected by loss of CCR7 ligands. The adoptive transfer of in vitro-generated Th17 cells from DLN cells of MOG(35-55)-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.
Keywords:Chemokine CCL19, Chemokine CCL21, Dendritic Cells, Experimental Autoimmune Encephalomyelitis, Interleukin-17, Interleukin-23 Subunit p19, Ligands, CCR7 Receptors, Helper-Inducer T-Lymphocytes, Animals, Mice
Source:Journal of Immunology
ISSN:0022-1767
Publisher:American Association of Immunologists (U.S.A.)
Volume:183
Number:4
Page Range:2513-2521
Date:15 August 2009
Official Publication:https://doi.org/10.4049/jimmunol.0800729
PubMed:View item in PubMed

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