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

ABSTRACT: Protein kinase C ? (PKC?) 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 PKC? 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 PKC?-deficient CD4+ T cells show normal Th17 marker gene expression (interleukin 17A/F, ROR?t), accompanied by enhanced production of the Th1-typical markers such as interferon gamma (IFN-?) and transcription factor T-bet. Mechanistically, this phenotype was linked to aberrantly elevated Stat4 mRNA levels in PKC?-/- 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 PKC?-deficient mice during the course of EAE. Taken together, our data provide genetic evidence that PKC? is critical for stabilizing Th17 cell phenotype by selective suppression of the STAT4/IFN-?/T-bet axis at the onset of differentiation.

SUBMITTER: Wachowicz K 

PROVIDER: S-EPMC4008503 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature