Meisel, Marlies, Hermann-Kleiter, Natascha, Hinterleitner, Reinhard, Gruber, Thomas, Wachowicz, Katarzyna, Pfeifhofer-Obermair, Christa, Fresser, Friedrich, Leitges, Michael, Soldani, Cristiana, Viola, Antonella, Kaminski, Sandra, and Baier, Gottfried
Summary: Transforming growth-factor β (TGFβ) has been implicated in T helper 17 (Th17) cell biology and in triggering expression of interleukin-17A (IL-17A), which is a key Th17 cell cytokine. Deregulated TGFβ receptor (TGFβR) signaling has been implicated in Th17-cell-mediated autoimmune pathogenesis. Nevertheless, the full molecular mechanisms involved in the activation of the TGFβR pathway in driving IL-17A expression remain unknown. Here, we identified protein kinase C α (PKCα) as a signaling intermediate specific to the Th17 cell subset in the activation of TGFβRI. We have shown that PKCα physically interacts and functionally cooperates with TGFβRI to promote robust SMAD2-3 activation. Furthermore, PKCα-deficient (Prkca −/− ) cells demonstrated a defect in SMAD-dependent IL-2 suppression, as well as decreased STAT3 DNA binding within the Il17a promoter. Consistently, Prkca −/− cells failed to mount appropriate IL-17A, but not IL-17F, responses in vitro and were resistant to induction of Th17-cell-dependent experimental autoimmune encephalomyelitis in vivo. [ABSTRACT FROM AUTHOR]