Protein Kinase C-θ Inhibits Inducible Regulatory T Cell Differentiation via an AKT-Foxo1/3a-Dependent Pathway

Protein kinase C (PKC)-theta has been shown to be a critical TCR signaling molecule that promotes the activation and differentiation of naive T cells into inflammatory effector T cells. In this study, we demonstrate that PKC-theta-mediated signals inhibit inducible regulatory T cell (iTreg) differentiation via an AKT-Foxo1/3A pathway. TGF-beta induced iTreg differentiation was enhanced in PKC-theta(-/-) T cells or wild-type cells treated with a specific PKC-theta inhibitor, but was inhibited by the PKC-theta activator PMA, or by CD28 crosslinking, which enhances PKC-theta activation. PKC-theta(-/-) T cells had reduced activity of the AKT kinase, and the expression of a constitutively active form of AKT in PKC-theta(-/-) T cells restored the 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-theta(-/-) T cells accordingly, indicating that the AKT-Foxo1/3A pathway is responsible for the inhibition of iTreg differentiation of iTregs downstream of PKC-theta. We conclude that PKC-theta is able to control T cell-mediated immune responses by shifting the balance between the differentiation of effector T cells and inhibitory Tregs. The Journal of Immunology, 2012, 188: 5337-5347.