Abstract
IL-12 was thought to be involved in the development of experimental autoimmune encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disorder of the CNS. However, we have recently found that IL-12 responsiveness, via IL-12Rbeta2, is not required in the induction of EAE. To determine the role of IL-12Rbeta1, a key subunit for the responsiveness to both IL-12 and IL-23, in the development of autoimmune diseases, we studied EAE in mice deficient in this subunit of IL-12R. IL-12Rbeta1(-/-) mice are completely resistant to myelin oligodendrocyte glycoprotein (MOG)-induced EAE, with an autoantigen-specific Th2 response. To study the mechanism underlying this Th2 bias, we cocultured purified CD4(+) T cells and APCs of MOG-immunized mice. We demonstrate that IL-12Rbeta1(-/-) APCs drive CD4(+) T cells of both wild-type and IL-12Rbeta1(-/-) mice to an Ag-induced Th2 phenotype, whereas wild-type APCs drive these CD4(+) T cells toward a Th1 type. IL-12Rbeta1(-/-) CD4(+) T cells, in turn, appear to exert an immunoregulatory effect on the capacity of wild-type APCs to produce IFN-gamma and TNF-alpha. Furthermore, decreased levels of IL-12p40, p35, and IL-23p19 mRNA expression were found in IL-12Rbeta1(-/-) APCs, indicating an autocrine pathway of IL-12/IL-23 via IL-12Rbeta1. IL-18 production and IL-18Ralpha expression are also significantly decreased in IL-12Rbeta1(-/-) mice immunized with MOG. We conclude that in the absence of IL-12Rbeta1, APCs play a prominent regulatory role in the induction of autoantigen-specific Th2 cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
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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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / pathology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Movement / genetics
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Cell Movement / immunology
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Cells, Cultured
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Coculture Techniques
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Down-Regulation / genetics
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Down-Regulation / immunology
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology*
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Female
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Glycoproteins / antagonists & inhibitors
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Glycoproteins / immunology
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Immunity, Innate / genetics
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Interleukin-12 / biosynthesis
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Interleukin-12 / genetics
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Interleukin-12 / metabolism*
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Interleukin-12 Subunit p35
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Interleukin-23
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Interleukin-23 Subunit p19
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Interleukins / biosynthesis
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Interleukins / genetics
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Monocytes / immunology
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Monocytes / pathology
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / immunology
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Protein Subunits / biosynthesis
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Protein Subunits / genetics
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RNA, Messenger / biosynthesis
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Receptors, Interleukin / deficiency
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Receptors, Interleukin / genetics
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Receptors, Interleukin / physiology*
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Receptors, Interleukin-12
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Spinal Cord / immunology
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Spinal Cord / pathology
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th2 Cells / cytology
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Th2 Cells / immunology
Substances
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Glycoproteins
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Il23a protein, mouse
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Interleukin-12 Subunit p35
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Interleukin-23
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Interleukin-23 Subunit p19
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Interleukins
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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Protein Subunits
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RNA, Messenger
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Receptors, Interleukin
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Receptors, Interleukin-12
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myelin oligodendrocyte glycoprotein (35-55)
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Interleukin-12