1. Protein kinase C θ regulates the phenotype of murine CD4+ Th17 cells.
- Author
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Wachowicz K, Hermann-Kleiter N, Meisel M, Siegmund K, Thuille N, and Baier G
- Subjects
- Animals, Blotting, Western, CD4-Positive T-Lymphocytes metabolism, Cell Differentiation genetics, Cells, Cultured, Encephalomyelitis, Autoimmune, Experimental genetics, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental metabolism, Female, Flow Cytometry, Interferon-gamma genetics, Interferon-gamma immunology, Interferon-gamma metabolism, Interferon-gamma pharmacology, Interleukin-17 immunology, Interleukin-17 metabolism, Interleukin-23 immunology, Interleukin-23 pharmacology, Isoenzymes deficiency, Isoenzymes genetics, Mice, Knockout, Myelin-Oligodendrocyte Glycoprotein immunology, Peptide Fragments immunology, Phenotype, Phosphorylation immunology, Protein Kinase C deficiency, Protein Kinase C genetics, Protein Kinase C-theta, Reverse Transcriptase Polymerase Chain Reaction, STAT1 Transcription Factor immunology, STAT1 Transcription Factor metabolism, STAT4 Transcription Factor immunology, STAT4 Transcription Factor metabolism, T-Box Domain Proteins genetics, T-Box Domain Proteins immunology, Th1 Cells immunology, Th1 Cells metabolism, Th17 Cells metabolism, CD4-Positive T-Lymphocytes immunology, Cell Differentiation immunology, Isoenzymes immunology, Protein Kinase C immunology, Th17 Cells immunology
- 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.
- Published
- 2014
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