PKC-θ shifts balance between inflammatory and regulatory T cells (123.42)

We demonstrate here that PKC-θ is a critical molecule to maintain immunological balance by shifting the ratio of inflammatory Th17 and inhibitory Treg cells. TGFβ-induced T regulatory cell (iTreg) differentiation was enhanced in naive PKC-θ -/- T cells or WT cells treated with a specific PKC-θ inhibitor. PKC-θ -/- T cells had reduced activity of the AKT kinase, and the expression of a constitutively active form of AKT in PKC-θ -/- T cells restored ability to inhibit iTreg differentiation. Furthermore, knockdown or overexpression of the AKT downstream targets FoxO1 and FoxO3a was found to inhibit or promote iTreg differentiation in PKC-θ -/- T cells, indicating that the AKT-FoxO1/3A pathway plays an inhibitory role in the differentiation of iTreg downstream of PKC-θ. In the other hand, we show that naive PKC-θ -/- T cells were defective in Th17 differentiation in vitro, whereas in vitro differentiation of Th1 and Th2 appeared normal. PKC-θ -/- T cells had notably lower levels of Stat3, a transcription factor required for Th17 differentiation. PKC-θ-mediated activation of the Stat3 promoter was inhibited by dominant negative AP-1 and IκB kinase β mutations, but stimulated by WT AP-1 and IκB kinase β, suggesting that PKC-θ stimulates Stat3 transcription via the AP-1 and NF-κB pathways. We conclude that PKC-θ is able to control T cell-mediated immune responses by shifting the balance between the differentiation of Th17 inflammatory and regulatory T cells.