Abstract
Dendritic cells (DCs) have been suggested to direct a type of Th differentiation through their cytokine profile, e.g., high IL-12/IL-23 for Th1 (named DC1/immunogenic DCs) and IL-10 for Th2 (DC2/tolerogenic DCs). Suppressor of cytokine signaling (SOCS)-3 is a potent inhibitor of Stat3 and Stat4 transduction pathways for IL-23 and IL-12, respectively. We thus hypothesize that an enhanced SOCS-3 expression in DCs may block the autocrine response of IL-12/IL-23 in these cells, causing them to become a DC2-type phenotype that will subsequently promote Th2 polarization of naive T cells. Indeed, in the present study we found that bone marrow-derived DCs transduced with SOCS-3 significantly inhibited IL-12-induced activation of Stat4 and IL-23-induced activation of Stat3. These SOCS-3-transduced DCs expressed a low level of MHC class II and CD86 on their surface, produced a high level of IL-10 but low levels of IL-12 and IFN-gamma, and expressed a low level of IL-23 p19 mRNA. Functionally, SOCS-3-transduced DCs drove naive myelin oligodendrocyte glycoprotein-specific T cells to a strong Th2 differentiation in vitro and in vivo. Injection of SOCS-3-transduced DCs significantly suppressed experimental autoimmune encephalomyelitis, a Th1 cell-mediated autoimmune disorder of the CNS and an animal model of multiple sclerosis. These results indicate that transduction of SOCS-3 in DCs is an effective approach to generating tolerogenic/DC2 cells that then skew immune response toward Th2, thus possessing therapeutic potential in Th1-dominant autoimmune disorders such as multiple sclerosis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cells, Cultured
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Coculture Techniques
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism*
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Dendritic Cells / transplantation
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / prevention & control
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Female
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Gene Expression Regulation / immunology
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Immune Tolerance / genetics*
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Immunophenotyping*
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Interleukin-12 / antagonists & inhibitors
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Interleukin-12 / physiology
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Interleukin-23
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Interleukin-23 Subunit p19
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Interleukins / antagonists & inhibitors
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Interleukins / physiology
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Lipopolysaccharides / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Molecular Sequence Data
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / metabolism
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STAT4 Transcription Factor / antagonists & inhibitors
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STAT4 Transcription Factor / metabolism
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Signal Transduction / genetics
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Signal Transduction / immunology
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / biosynthesis
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Suppressor of Cytokine Signaling Proteins / genetics*
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Suppressor of Cytokine Signaling Proteins / physiology
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Th2 Cells / cytology
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Th2 Cells / immunology*
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Transduction, Genetic*
Substances
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Il23a protein, mouse
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Interleukin-23
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Interleukin-23 Subunit p19
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Interleukins
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Lipopolysaccharides
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STAT3 Transcription Factor
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STAT4 Transcription Factor
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Socs3 protein, mouse
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Stat3 protein, mouse
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Stat4 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Interleukin-12