Protein Kinase C-{theta} 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) diff...

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Veröffentlicht in:The Journal of immunology (1950) 2012-06, Vol.188 (11), p.5337-5347
Hauptverfasser: Ma, Jian, Ding, Yan, Fang, Xianfeng, Wang, Ruiqing, Sun, Zuoming
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Sprache:eng
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Zusammenfassung: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.
ISSN:0022-1767
DOI:10.4049/jimmunol.1102979