Abstract
IFN-gamma- and IL-17-producing T cells autoreactive across myelin components are central to the pathogenesis of multiple sclerosis. Using direct in vivo, adoptive transfer, and in vitro systems, we show in this study that the generation of these effectors in myelin oligodendrocyte glycoprotein(35-55)-induced experimental autoimmune encephalomyelitis depends on interactions of locally produced C3a/C5a with APC and T cell C3aR/C5aR. In the absence of the cell surface C3/C5 convertase inhibitor decay-accelerating factor (DAF), but not the combined absence of DAF and C5aR and/or C3aR on APC and T cells, a heightened local autoimmune response occurs in which myelin destruction is markedly augmented in concert with markedly more IFN-gamma(+) and IL-17(+) T cell generation. The augmented T cell response is due to increased IL-12 and IL-23 elaboration by APCs together with increased T cell expression of the receptors for each cytokine. The results apply to initial generation of the IL-17 phenotype because naive CD62L(high) Daf1(-/-) T cells produce 3-fold more IL-17 in response to TGF-beta and IL-6, whereas CD62L(high) Daf1(-/-)C5aR(-/-)C3aR(-/-) T cells produce 4-fold less.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigen-Presenting Cells / immunology*
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Antigen-Presenting Cells / metabolism
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CD55 Antigens / immunology
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CD55 Antigens / metabolism
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Complement C3-C5 Convertases / immunology
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Complement C3-C5 Convertases / metabolism
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Complement C3a / immunology*
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Complement C3a / metabolism
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Complement C5a / immunology*
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Complement C5a / metabolism
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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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Glycoproteins / immunology
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Glycoproteins / pharmacology
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Interferon-gamma / biosynthesis
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Interferon-gamma / immunology*
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Interleukin-12 / immunology
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Interleukin-12 / metabolism
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Interleukin-17 / biosynthesis
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Interleukin-17 / immunology*
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Interleukin-23 / immunology
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Interleukin-23 / metabolism
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Interleukin-6 / immunology
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Interleukin-6 / metabolism
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Mice
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Mice, Knockout
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Multiple Sclerosis / immunology*
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Multiple Sclerosis / metabolism
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Myelin Sheath / immunology
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Myelin Sheath / metabolism
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments / immunology
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Peptide Fragments / pharmacology
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Rats
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Receptor, Anaphylatoxin C5a / immunology
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Receptor, Anaphylatoxin C5a / metabolism
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
Substances
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CD55 Antigens
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Glycoproteins
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Interleukin-17
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Interleukin-23
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Interleukin-6
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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Receptor, Anaphylatoxin C5a
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myelin oligodendrocyte glycoprotein (35-55)
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Interleukin-12
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Complement C3a
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Complement C5a
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Interferon-gamma
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Complement C3-C5 Convertases