PKC-θ inhibits iTreg differentiation via an AKT-FoxO1/3a-dependent pathway

Protein Kinase C-θ (PKC-θ) has been shown to be a critical T cell receptor (TCR) signaling molecule that promotes the activation and differentiation of naïve T cells into inflammatory effector T cells. We demonstrate here that PKC-θ-mediated signals inhibit iTreg differentiation via an AKT-Forkhead Box O1/3a (FoxO1/3A) pathway. Transforming growth factor β-induced iTreg differentiation was enhanced in PKC-θ −/− T cells or WT cells treated with a specific PKC-θ inhibitor, but was inhibited by the PKC-θ activator PMA, or by CD28 crosslinking which enhances PKC-θ activation. 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 over expression of the AKT downstream targets FoxO1 and FoxO3a was found to inhibit or promote iTreg differentiation in PKC-θ −/− T cells accordingly, indicating that the AKT-FoxO1/3A pathway is responsible for the inhibition of iTreg differentiation of iTreg downstream of PKC-θ. We conclude that PKC-θ is able to control T cell-mediated immune responses by shifting the balance between the differentiation of effector T cells and inhibitory Tregs.