Abstract
Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) require exposure to IL-23 to become encephalitogenic, but the mechanism by which IL-23 promotes their pathogenicity is not known. Here we found that IL-23 induced production of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) in T(H)17 cells and that GM-CSF had an essential role in their encephalitogenicity. Our findings identify a chief mechanism that underlies the important role of IL-23 in autoimmune diseases. IL-23 induced a positive feedback loop whereby GM-CSF secreted by T(H)17 cells stimulated the production of IL-23 by antigen-presenting cells. Such cross-regulation of IL-23 and GM-CSF explains the similar pattern of resistance to autoimmunity when either of the two cytokines is absent and identifies T(H)17 cells as a crucial source of GM-CSF in autoimmune inflammation.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antibodies / immunology
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Antibodies / pharmacology
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CD11c Antigen / immunology
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CD11c Antigen / metabolism
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cells, Cultured
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Coculture Techniques
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Encephalomyelitis, Autoimmune, Experimental / chemically induced
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / metabolism*
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Female
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Flow Cytometry
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Glycoproteins
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Granulocyte-Macrophage Colony-Stimulating Factor / genetics
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Granulocyte-Macrophage Colony-Stimulating Factor / immunology
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
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Interleukin-1 / pharmacology*
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Interleukin-1beta / pharmacology
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Interleukin-23 / immunology
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Interleukin-23 / metabolism
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Interleukin-23 / pharmacology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Myelin-Oligodendrocyte Glycoprotein
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Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
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Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
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Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
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Peptide Fragments
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Th1 Cells / drug effects
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th17 Cells / drug effects*
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Th17 Cells / immunology
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Th17 Cells / metabolism
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Transforming Growth Factor beta / pharmacology
Substances
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Antibodies
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CD11c Antigen
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Glycoproteins
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Interleukin-1
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Interleukin-1beta
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Interleukin-23
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Myelin-Oligodendrocyte Glycoprotein
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Nuclear Receptor Subfamily 1, Group F, Member 3
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Peptide Fragments
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Transforming Growth Factor beta
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myelin oligodendrocyte glycoprotein (35-55)
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Granulocyte-Macrophage Colony-Stimulating Factor