Protein kinase C θ regulates the phenotype of murine CD4+ Th17 cells

PLoS One. 2014 May 2;9(5):e96401. doi: 10.1371/journal.pone.0096401. eCollection 2014.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • 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
  • Isoenzymes / immunology*
  • Mice, Knockout
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Peptide Fragments / immunology
  • Phenotype
  • Phosphorylation / immunology
  • Protein Kinase C / deficiency
  • Protein Kinase C / genetics
  • Protein Kinase C / immunology*
  • 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 / immunology*
  • Th17 Cells / metabolism


  • Interleukin-17
  • Interleukin-23
  • Isoenzymes
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • STAT1 Transcription Factor
  • STAT4 Transcription Factor
  • Stat1 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • myelin oligodendrocyte glycoprotein (35-55)
  • Interferon-gamma
  • Prkcq protein, mouse
  • Protein Kinase C
  • Protein Kinase C-theta