Abstract
Protein kinase C θ (PKCθ) is involved in signaling downstream of the T cell antigen receptor (TCR) and is important for shaping effector T cell functions and inflammatory disease development. Acquisition of Th1-like effector features by Th17 cells has been linked to increased pathogenic potential. However, the molecular mechanisms underlying Th17/Th1 phenotypic instability remain largely unknown. In the current study, we address the role of PKCθ in differentiation and function of Th17 cells by using genetic knock-out mice. Implementing in vitro (polarizing T cell cultures) and in vivo (experimental autoimmune encephalomyelitis model, EAE) techniques, we demonstrated that PKCθ-deficient CD4+ T cells show normal Th17 marker gene expression (interleukin 17A/F, RORγt), accompanied by enhanced production of the Th1-typical markers such as interferon gamma (IFN-γ) and transcription factor T-bet. Mechanistically, this phenotype was linked to aberrantly elevated Stat4 mRNA levels in PKCθ-/- CD4+ T cells during the priming phase of Th17 differentiation. In contrast, transcription of the Stat4 gene was suppressed in Th17-primed wild-type cells. This change in cellular effector phenotype was reflected in vivo by prolonged neurological impairment of PKCθ-deficient mice during the course of EAE. Taken together, our data provide genetic evidence that PKCθ is critical for stabilizing Th17 cell phenotype by selective suppression of the STAT4/IFN-γ/T-bet axis at the onset of differentiation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cells, Cultured
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Encephalomyelitis, Autoimmune, Experimental / genetics
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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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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interferon-gamma / pharmacology
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Interleukin-23 / immunology
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Interleukin-23 / pharmacology
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Isoenzymes / deficiency
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Isoenzymes / genetics
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Isoenzymes / immunology*
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Mice, Knockout
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Myelin-Oligodendrocyte Glycoprotein / immunology
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Peptide Fragments / immunology
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Phenotype
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Phosphorylation / immunology
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Protein Kinase C / deficiency
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Protein Kinase C / genetics
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Protein Kinase C / immunology*
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Protein Kinase C-theta
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Reverse Transcriptase Polymerase Chain Reaction
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STAT1 Transcription Factor / immunology
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STAT1 Transcription Factor / metabolism
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STAT4 Transcription Factor / immunology
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STAT4 Transcription Factor / metabolism
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th17 Cells / immunology*
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Th17 Cells / metabolism
Substances
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Interleukin-17
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Interleukin-23
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Isoenzymes
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Myelin-Oligodendrocyte Glycoprotein
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Peptide Fragments
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STAT1 Transcription Factor
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STAT4 Transcription Factor
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Stat1 protein, mouse
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T-Box Domain Proteins
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T-box transcription factor TBX21
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myelin oligodendrocyte glycoprotein (35-55)
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Interferon-gamma
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Prkcq protein, mouse
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Protein Kinase C
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Protein Kinase C-theta