Protein Kinase C θ Regulates the Phenotype of Murine CD4⁺ Th17 Cells

<div><p>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 <i>in vitro</i> (polarizing T cell cultures) and <i>in vivo</i> (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 <i>Stat4</i> mRNA levels in PKCθ^−/− CD4⁺ T cells during the priming phase of Th17 differentiation. In contrast, transcription of the <i>Stat4</i> gene was suppressed in Th17-primed wild-type cells. This change in cellular effector phenotype was reflected <i>in vivo</i> 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.</p>