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Protein Kinase B/Akt Signals Impair Th17 Differentiation and Support Natural Regulatory T Cell Function and Induced Regulatory T Cell Formation¹

Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany

Protein kinase B (PKB)/Akt signals control T cell proliferation and differentiation but their effect on the generation and function of regulatory T cells (Treg) and Th17 cells is not well understood. In this study, we show that elevated PKB signals antagonize the immunosuppressive effect of TGF-β1 on cell size, CD25 and CD98 expression, and proliferation of CD3-stimulated naive CD4⁺ T cells from wild-type and CD28-deficient mice. Conventional CD4⁺ T cells expressing active PKB are less susceptible to suppression by natural regulatory T cells. Although PKB signals do not affect the development of natural regulatory T cells, they enhance their suppressor capacity. Upon TCR triggering and TGF-β1 costimulation, wild-type and CD28-deficient CD4⁺ T cells transgenic for PKB readily express Foxp3, thereby acquiring suppressor capacity. These effects of elevated PKB signals on T cell function involve a marked and sustained activation of STAT5 and Foxp3 and reduction in nuclear NFATc1 levels. In contrast, PKB signals impair TGF-β1/IL-6-mediated differentiation of naive CD4⁺ T cells into the Th17 lineage. This correlates with an increased signaling of ERK, STAT5, and STAT6. Finally, elevated PKB signals reduced the severity of experimental autoimmune encephalomyelitis in wild-type mice but induced experimental autoimmune encephalomyelitis in mice deficient for CD28. Altogether, these data indicate an important role of PKB signals on control of TGF-β1-mediated T cell responses and, thereby, on tolerizing and inflammatory immune processes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Deutsche Forschungsgemeinschaft (BO1054/2-1) and Land Sachsen-Anhalt (N2/ND; to U.B.).

² M.P. and S.E. contributed equally to this work and should be considered co-first authors.

³ Address correspondence and reprint requests to Dr. Ursula Bommhardt, Institute of Medical and Clinical Immunology, Otto-von-Guericke University Magdeburg, Leipzigerstrasse 44, D-39120 Magdeburg, Germany. E-mail address: ursula.bommhardt{at}med.ovgu.de

⁴ Abbreviations used in this paper: Treg, regulatory T cell; iTreg, induced Treg; nTreg, natural Treg; PKB, protein kinase B; myrPKB, myristoylated PKB; tg, transgenic; Teff, effector T cell; EAE, experimental autoimmune encephalomyelitis; mTOR, mammalian target of rapamycin; wt, wild type; pERK, phosphorylated ERK; MOG, myelin oligodendrocyte glycoprotein; IFR4, IFN regulatory factor 4; MFI, mean fluorescence intensity; GITR, glucocorticoid-induced TNFR-related protein; RORt, retinoid-related orphan receptor gamma; PTEN, phosphatase and tensin homologue.