Protein Kinase C-[thetas] Promotes Th17 Differentiation via Upregulation of Stat3

• Published in: The Journal of immunology (1950) 2012-06, Vol.188 (12), p.5887-5897
• Main Authors: Kwon, Myung-Ja, Ma, Jian, Ding, Yan, Wang, Ruiqing, Sun, Zuoming
• Format: Article
• Language: English
• ISSN: 0022-1767
• DOI: 10.4049/jimmunol.1102941

Although protein kinase C-[thetas] (PKC-[thetas])-deficient mice are resistant to the induction of Th17-dependent experimental autoimmune encephalomyelitis, the function of PKC-[thetas] in Th17 differentiation remains unknown. In this article, we show that purified, naive CD4 PKC-[thetas]-/- T cells were defective in Th17 differentiation, whereas Th1 and Th2 differentiation appeared normal. Activation of PKC-[thetas] with PMA promoted Th17 differentiation in wild type (WT) but not PKC-[thetas]-/- T cells. Furthermore, PKC-[thetas]-/- T cells had notably lower levels of Stat3, a transcription factor required for Th17 differentiation, and PMA markedly stimulated the expression of Stat3 in WT but not PKC-[thetas]-/- T cells. In contrast, activation of Stat4 and Stat6, which are critical for Th1 and Th2 differentiation, was normal in PKC-[thetas]-/- T cells. Forced expression of Stat3 significantly increased Th17 differentiation in PKC-[thetas]-/- T cells, suggesting that reduced Stat3 levels were responsible for impaired Th17 differentiation, and that Stat3 lies downstream of PKC-[thetas]. Constitutively active PKC-[thetas], or WT PKC-[thetas] activated by either PMA or TCR cross-linking, stimulated expression of a luciferase reporter gene driven by the Stat3 promoter. PKC-[thetas]-mediated activation of the Stat3 promoter was inhibited by dominant-negative AP-1 and I Kappa B kinase- beta , but stimulated by WT AP-1 and I Kappa B kinase- beta , suggesting that PKC-[thetas] stimulates Stat3 transcription via the AP-1 and NF- Kappa B pathways. Lastly, conditions favoring Th17 differentiation induced the highest activation level of PKC-[thetas]. Altogether, the data indicate that PKC-[thetas] integrates the signals from TCR signaling and Th17 priming cytokines to upregulate Stat3 via NF- Kappa B and AP-1, resulting in the stimulation of Th17 differentiation.