Abstract
IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. Gene array analysis on Stat6 and T-bet double-deficient Th17 cells identified the Th2 transcription factor c-Maf to be synergistically up-regulated by IL-6 plus TGFbeta and associated with Th17 IL-10 production. Both c-Maf and IL-10 induction during Th17 polarization depended on Stat3, but not Stat6 or Stat1, and mechanistically differed from IL-10 regulation by Th2 or IL-27 signals. TGFbeta was also synergistic with IL-27 to induce c-Maf, and it induced Stat1-independent IL-10 expression in contrast to IL-27 alone. Retroviral transduction of c-Maf was able to induce IL-10 expression in Stat6-deficient CD4 and CD8 T cells, and c-Maf directly transactivated IL-10 gene expression through binding to a MARE (Maf recognition element) motif in the IL-10 promoter. Taken together, these data reveal a novel role for c-Maf in regulating T effector development, and they suggest that TGFbeta may antagonize Th17 immunity by IL-10 production through c-Maf induction.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Blotting, Western
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Electrophoretic Mobility Shift Assay
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Gene Expression
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Interleukin-10 / biosynthesis*
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Interleukin-10 / immunology
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Interleukin-6 / immunology
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Interleukin-6 / metabolism
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Lymphocyte Activation
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Mice
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Mice, Knockout
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Oligonucleotide Array Sequence Analysis
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Proto-Oncogene Proteins c-maf / immunology*
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Proto-Oncogene Proteins c-maf / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor / immunology
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STAT3 Transcription Factor / metabolism
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T-Box Domain Proteins / immunology
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T-Box Domain Proteins / metabolism
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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Transforming Growth Factor beta / immunology*
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Transforming Growth Factor beta / metabolism
Substances
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Interleukin-17
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Interleukin-6
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Proto-Oncogene Proteins c-maf
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STAT3 Transcription Factor
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Transforming Growth Factor beta
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Interleukin-10