The balancing act of AKT in T cells

Abstract

The serine/threonine-specific protein kinase AKT is gaining recognition as a major crossroad in numerous cellular signaling pathways through its ability to regulate cell differentiation, proliferation, survival and metabolism. This review focuses on the recent advances in AKT signaling and downstream events in T cells, emphasizing its contrasting role in conventional and regulatory (Treg) T cell populations. Activation of AKT has been known for many years to be critical in the development and function of conventional T cells. However, it has just recently been uncovered that AKT exerts an inhibitory effect on Treg generation and suppressor function. These studies have placed AKT at the nexus of Treg development and function, thus opening novel avenues for therapeutic manipulation.

Keywords

AKT / Tregs / T cell signaling / T cell differentiation

References

[1] Akbar A N, Vukmanovic-Stejic M, Taams L S, Macallan D C (2007). The dynamic co-evolution of memory and regulatory CD4+ T cells in the periphery. Nat Rev Immunol, 7(3): 231–237

[2] Alessi D R, Cohen P (1998). Mechanism of activation and function of protein kinase B. Curr Opin Genet Dev, 8(1): 55–62

[3] Alessi D R, Pearce L R, García-Martínez J M (2009). New insights into mTOR signaling: mTORC2 and beyond. Sci Signal, 2(67): pe27

[4] Altomare D A, Guo K, Cheng J Q, Sonoda G, Walsh K, Testa J R (1995). Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene. Oncogene, 11(6): 1055–1060

[5] Andjelković M, Jakubowicz T, Cron P, Ming X F, Han J W, Hemmings B A (1996). Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors. Proc Natl Acad Sci USA, 93(12): 5699–5704

[6] Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa T C, Cumano A, Bandeira A (2001). CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol, 166(5): 3008–3018

[6a] Apostolou I, Sarukhan A, Klein L, von Boehmer H (2002). Origin of regulcdory T cells with known specificity for antigen. Nat Immunol, 3(8): 756–763

[7] Arimura Y, Shiroki F, Kuwahara S, Kato H, Dianzani U, Uchiyama T, Yagi J (2004). Akt is a neutral amplifier for Th cell differentiation. J Biol Chem, 279(12): 11408–11416

[8] Balendran A, Casamayor A, Deak M, Paterson A, Gaffney P, Currie R, Downes C P, Alessi D R (1999). PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Curr Biol, 9(8): 393–404

[9] Beals C R, Sheridan C M, Turck C W, Gardner P, Crabtree G R (1997). Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science, 275(5308): 1930–1933

[10] Bellacosa A, Testa J R, Staal S P, Tsichlis P N (1991). A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science, 254(5029): 274–277

[11] Bluestone J A, Abbas A K (2003). Natural versus adaptive regulatory T cells. Nat Rev Immunol, 3(3): 253–257

[12] Bopp T, Palmetshofer A, Serfling E, Heib V, Schmitt S, Richter C, Klein M, Schild H, Schmitt E, Stassen M (2005). NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4⁺ T lymphocytes by CD4⁺ CD25⁺ regulatory T cells. J Exp Med, 201(2): 181–187

[13] Brodbeck D, Cron P, Hemmings B A (1999). A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. J Biol Chem, 274(14): 9133–9136

[14] Brognard J, Sierecki E, Gao T, Newton A C (2007). PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell, 25(6): 917–931

[15] Brunet A, Bonni A, Zigmond M J, Lin M Z, Juo P, Hu L S, Anderson M J, Arden K C, Blenis J, Greenberg M E (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell, 96(6): 857–868

[16] Brunkow M E, Jeffery E W, Hjerrild K A, Paeper B, Clark L B, Yasayko S A, Wilkinson J E, Galas D, Ziegler S F, Ramsdell F (2001). Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet, 27(1): 68–73

[17] Burgering B M, Coffer P J (1995). Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature, 376(6541): 599–602

[18] Burgering B M, Kops G J (2002). Cell cycle and death control: long live Forkheads. Trends Biochem Sci, 27(7): 352–360

[19] Cantley L C, Neel B G (1999). New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA, 96(8): 4240–4245

[20] Cardone M H, Roy N, Stennicke H R, Salvesen G S, Franke T F, Stanbridge E, Frisch S, Reed J C (1998). Regulation of cell death protease caspase-9 by phosphorylation. Science, 282(5392): 1318–1321

[21] Carpenter C L, Cantley L C (1996). Phosphoinositide kinases. Curr Opin Cell Biol, 8(2): 153–158

[22] Chen C, Edelstein L C, Gélinas C (2000). The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol Cell Biol, 20(8): 2687–2695

[23] Cheng J Q, Godwin A K, Bellacosa A, Taguchi T, Franke T F, Hamilton T C, Tsichlis P N, Testa J R (1992). AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci USA, 89(19): 9267–9271

[24] Coffer P J, Woodgett J R (1991). Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem, 201(2): 475–481

[25] Conery A R, Cao Y, Thompson E A, Townsend C M Jr, Ko T C, Luo K (2004). Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol, 6(4): 366–372

[26] Coombes J L, Siddiqui K R, Arancibia-Cárcamo C V, Hall J, Sun C M, Belkaid Y, Powrie F (2007). A functionally specialized population of mucosal CD103⁺ DCs induces Foxp3⁺ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med, 204(8): 1757–1764

[27] Crellin N K, Garcia R V, Levings M K (2007). Altered activation of AKT is required for the suppressive function of human CD4⁺CD25⁺ T regulatory cells. Blood, 109(5): 2014–2022

[28] Datta S R, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg M E (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 91(2): 231–241

[29] del Peso L, González-García M, Page C, Herrera R, Nuñez G (1997). Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science, 278(5338): 687–689

[30] Du K, Montminy M (1998). CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem, 273(49): 32377–32379

[31] Duarte J H, Zelenay S, Bergman M L, Martins A C, Demengeot J (2009). Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol, 39(4): 948–955

[32] Dummler B, Hemmings B A (2007). Physiological roles of PKB/Akt isoforms in development and disease. Biochem Soc Trans, 35(2): 231–235

[33] Feuerer M, Hill J A, Mathis D, Benoist C (2009). Foxp3⁺ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol, 10(7): 689–695

[34] Fontenot J D, Gavin M A, Rudensky A Y (2003). Foxp3 programs the development and function of CD4⁺CD25⁺ regulatory T cells. Nat Immunol, 4(4): 330–336

[35] Franke T F, Yang S I, Chan T O, Datta K, Kazlauskas A, Morrison D K, Kaplan D R, Tsichlis P N (1995). The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell, 81(5): 727–736

[36] Gao T, Furnari F, Newton A C (2005). PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell, 18(1): 13–24

[37] Godfrey D I, Kennedy J, Suda T, Zlotnik A (1993). A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J Immunol, 150(10): 4244–4252

[38] Gregori S, Giarratana N, Smiroldo S, Adorini L (2003). Dynamics of pathogenic and suppressor T cells in autoimmune diabetes development. J Immunol, 171(8): 4040–4047

[39] Hagenbeek T J, Naspetti M, Malergue F, Garçon F, Nunès J A, Cleutjens K B, Trapman J, Krimpenfort P, Spits H (2004). The loss of PTEN allows TCR alphabeta lineage thymocytes to bypass IL-7 and Pre-TCR-mediated signaling. J Exp Med, 200(7): 883–894

[40] Hanada M, Feng J, Hemmings B A (2004). Structure, regulation and function of PKB/AKT—a major therapeutic target. Biochim Biophys Acta, 1697(1-2): 3–16

[41] Harrington L S, Findlay G M, Lamb R F (2005). Restraining PI3K: mTOR signalling goes back to the membrane. Trends Biochem Sci, 30(1): 35–42

[42] Haxhinasto S, Mathis D, Benoist C (2008). The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med, 205(3): 565–574

[43] Hill M M, Andjelkovic M, Brazil D P, Ferrari S, Fabbro D, Hemmings B A (2001). Insulin-stimulated protein kinase B phosphorylation on Ser-473 is independent of its activity and occurs through a staurosporine-insensitive kinase. J Biol Chem, 276(28): 25643–25646

[44] Hinton H J, Alessi D R, Cantrell D A (2004). The serine kinase phosphoinositide-dependent kinase 1 (PDK1) regulates T cell development. Nat Immunol, 5(5): 539–545

[45] Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, Ueno Y, Hatch H, Majumder P K, Pan B S, Kotani H (2010). MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther, 9(7): 1956–1967

[46] Hoffman K, Holmes F A, Fraschini G, Esparza L, Frye D, Raber M N, Newman R A, Hortobagyi G N (1996). Phase I-II study: triciribine (tricyclic nucleoside phosphate) for metastatic breast cancer. Cancer Chemother Pharmacol, 37(3): 254–258

[47] Hori S (2010). Developmental plasticity of Foxp3⁺ regulatory T cells. Curr Opin Immunol, 22(5): 575–582

[48] Hori S, Nomura T, Sakaguchi S (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science, 299(5609): 1057–1061

[49] Horwitz D A, Zheng S G, Gray J D (2008). Natural and TGF-beta-induced Foxp3(+)CD4(+) CD25(+) regulatory T cells are not mirror images of each other. Trends Immunol, 29(9): 429–435

[50] Huang J, Manning B D (2009). A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans, 37(1): 217–222

[51] Jefferies H B, Fumagalli S, Dennis P B, Reinhard C, Pearson R B, Thomas G (1997). Rapamycin suppresses 5’TOP mRNA translation through inhibition of p70s6k. EMBO J, 16(12): 3693–3704

[52] Jones P F, Jakubowicz T, Pitossi F J, Maurer F, Hemmings B A (1991). Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. Proc Natl Acad Sci USA, 88(10): 4171–4175

[53] Josefowicz S Z, Rudensky A (2009). Control of regulatory T cell lineage commitment and maintenance. Immunity, 30(5): 616–625

[54] Juntilla M M, Koretzky G A (2008). Critical roles of the PI3K/Akt signaling pathway in T cell development. Immunol Lett, 116(2): 104–110

[55] Juntilla M M, Wofford J A, Birnbaum M J, Rathmell J C, Koretzky G A (2007). Akt1 and Akt2 are required for alphabeta thymocyte survival and differentiation. Proc Natl Acad Sci USA, 104(29): 12105–12110

[56] Kandel E S, Hay N (1999). The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res, 253(1): 210–229

[57] Kane L P, Andres P G, Howland K C, Abbas A K, Weiss A (2001). Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-gamma but not TH2 cytokines. Nat Immunol, 2(1): 37–44

[58] Kane L P, Shapiro V S, Stokoe D, Weiss A (1999). Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol, 9(11): 601–604

[59] Kawase T, Ohki R, Shibata T, Tsutsumi S, Kamimura N, Inazawa J, Ohta T, Ichikawa H, Aburatani H, Tashiro F, Taya Y (2009). PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt. Cell, 136(3): 535–550

[60] Khattri R, Cox T, Yasayko S A, Ramsdell F (2003). An essential role for Scurfin in CD4⁺CD25⁺ T regulatory cells. Nat Immunol, 4(4): 337–342

[61] Khoshnan A, Tindell C, Laux I, Bae D, Bennett B, Nel A E (2000). The NF-kappa B cascade is important in Bcl-xL expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4⁺ lymphocytes. J Immunol, 165(4): 1743–1754

[62] King C G, Kobayashi T, Cejas P J, Kim T, Yoon K, Kim G K, Chiffoleau E, Hickman S P, Walsh P T, Turka L A, Choi Y (2006). TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis. Nat Med, 12(9): 1088–1092

[63] Kleijn M, Scheper G C, Voorma H O, Thomas A A (1998). Regulation of translation initiation factors by signal transduction. Eur J Biochem, 253(3): 531–544

[64] Kojima H, Kanno Y, Hase H, Kobata T (2005). CD4⁺CD25⁺ regulatory T cells attenuate the phosphatidylinositol 3-kinase/Akt pathway in antigen-primed immature CD8+ CTLs during functional maturation. J Immunol, 174(10): 5959–5967

[65] Komatsu N, Mariotti-Ferrandiz M E, Wang Y, Malissen B, Waldmann H, Hori S (2009). Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA, 106(6): 1903–1908

[66] Konishi H, Kuroda S, Tanaka M, Matsuzaki H, Ono Y, Kameyama K, Haga T, Kikkawa U (1995). Molecular cloning and characterization of a new member of the RAC protein kinase family: association of the pleckstrin homology domain of three types of RAC protein kinase with protein kinase C subspecies and beta gamma subunits of G proteins. Biochem Biophys Res Commun, 216(2): 526–534

[67] Lafont V, Astoul E, Laurence A, Liautard J, Cantrell D (2000). The T cell antigen receptor activates phosphatidylinositol 3-kinase-regulated serine kinases protein kinase B and ribosomal S6 kinase 1. FEBS Lett, 486(1): 38–42

[68] Lee K, Gudapati P, Dragovic S, Spencer C, Joyce S, Killeen N, Magnuson M A, Boothby M (2010). Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity, 32(6): 743–753

[69] Levelt C N, Carsetti R, Eichmann K (1993a). Regulation of thymocyte development through CD3. II. Expression of T cell receptor beta CD3 epsilon and maturation to the CD4⁺8⁺ stage are highly correlated in individual thymocytes. J Exp Med, 178(6): 1867–1875

[70] Levelt C N, Ehrfeld A, Eichmann K (1993b). Regulation of thymocyte development through CD3. I. Timepoint of ligation of CD3 epsilon determines clonal deletion or induction of developmental program. J Exp Med, 177(3): 707–716

[71] Liao Y, Hung M C (2004). A new role of protein phosphatase 2a in adenoviral E1A protein-mediated sensitization to anticancer drug-induced apoptosis in human breast cancer cells. Cancer Res, 64(17): 5938–5942

[72] Livolsi A, Busuttil V, Imbert V, Abraham R T, Peyron J F (2001). Tyrosine phosphorylation-dependent activation of NF-kappa B. Requirement for p56 LCK and ZAP-70 protein tyrosine kinases. Eur J Biochem, 268(5): 1508–1515

[73] Madrid L V, Wang C Y, Guttridge D C, Schottelius A J, Baldwin A S Jr, Mayo M W (2000). Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappaB. Mol Cell Biol, 20(5): 1626–1638

[74] Maira S M, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chène P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, García-Echeverría C (2008). Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther, 7(7): 1851–1863

[75] Manning B D, Cantley L C (2007). AKT/PKB signaling: navigating downstream. Cell, 129(7): 1261–1274

[76] Mao C, Tili E G, Dose M, Haks M C, Bear S E, Maroulakou I, Horie K, Gaitanaris G A, Fidanza V, Ludwig T, Wiest D L, Gounari F, Tsichlis P N (2007). Unequal contribution of Akt isoforms in the double-negative to double-positive thymocyte transition. J Immunol, 178(9): 5443–5453

[77] Markman B, Dienstmann R, Tabernero J (2010). Targeting the PI3K/Akt/mTOR pathway—beyond rapalogs. Oncotarget, 1(7): 530–543

[78] Marone R, Cmiljanovic V, Giese B, Wymann M P (2008). Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim Biophys Acta, 1784(1): 159–185

[79] Mendoza M C, Blenis J (2007). PHLPPing it off: phosphatases get in the Akt. Mol Cell, 25(6): 798–800

[80] Monk C R, Spachidou M, Rovis F, Leung E, Botto M, Lechler R I, Garden O A (2005). MRL/Mp CD4⁺,CD25^- T cells show reduced sensitivity to suppression by CD4⁺,CD25⁺ regulatory T cells in vitro: a novel defect of T cell regulation in systemic lupus erythematosus. Arthritis Rheum, 52(4): 1180–1184

[81] Nakatani K, Sakaue H, Thompson D A, Weigel R J, Roth R A (1999). Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site. Biochem Biophys Res Commun, 257(3): 906–910

[82] O’Reilly K E, Rojo F, She Q B, Solit D, Mills G B, Smith D, Lane H, Hofmann F, Hicklin D J, Ludwig D L, Baselga J, Rosen N (2006). mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res, 66(3): 1500–1508

[83] Obata T, Yaffe M B, Leparc G G, Piro E T, Maegawa H, Kashiwagi A, Kikkawa R, Cantley L C (2000). Peptide and protein library screening defines optimal substrate motifs for AKT/PKB. J Biol Chem, 275(46): 36108–36115

[84] Oldenhove G, Bouladoux N, Wohlfert E A, Hall J A, Chou D, Dos Santos L, O’Brien S, Blank R, Lamb E, Natarajan S, Kastenmayer R, Hunter C, Grigg M E, Belkaid Y (2009). Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity, 31(5): 772–786

[85] Ozes O N, Mayo L D, Gustin J A, Pfeffer S R, Pfeffer L M, Donner D B (1999). NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature, 401(6748): 82–85

[86] Padmanabhan S, Mukhopadhyay A, Narasimhan S D, Tesz G, Czech M P, Tissenbaum H A (2009). A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell, 136(5): 939–951

[87] Pal S K, Reckamp K, Yu H, Figlin R A (2010). Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs, 19(11): 1355–1366

[88] Papiernik M, de Moraes M L, Pontoux C, Vasseur F, Pénit C (1998). Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency. Int Immunol, 10(4): 371– 378

[89] Parry R V, Reif K, Smith G, Sansom D M, Hemmings B A, Ward S G (1997). Ligation of the T cell co-stimulatory receptor CD28 activates the serine-threonine protein kinase protein kinase B. Eur J Immunol, 27(10): 2495–2501

[90] Patra A K, Drewes T, Engelmann S, Chuvpilo S, Kishi H, Hünig T, Serfling E, Bommhardt U H (2006). PKB rescues calcineurin/NFAT-induced arrest of Rag expression and pre-T cell differentiation. J Immunol, 177(7): 4567–4576

[91] Patterson S J, Han J M, Garcia R, Assi K, Gao T, O’Neill A, Newton A C, Levings M K (2011). Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells. J Immunol, 186(10): 5533–5537

[92] Peifer C, Alessi D R (2008). Small-molecule inhibitors of PDK1. ChemMedChem, 3(12): 1810–1838

[93] Penit C, Vasseur F (1989). Cell proliferation and differentiation in the fetal and early postnatal mouse thymus. J Immunol, 142(10): 3369–3377

[94] Pillai V, Karandikar N J (2007). Human regulatory T cells: a unique, stable thymic subset or a reversible peripheral state of differentiation? Immunol Lett, 114(1): 9–15

[95] Pim D, Massimi P, Dilworth S M, Banks L (2005). Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A. Oncogene, 24(53): 7830–7838

[96] Rao A, Luo C, Hogan P G (1997). Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol, 15(1): 707–747

[97] Redpath N T, Foulstone E J, Proud C G (1996). Regulation of translation elongation factor-2 by insulin via a rapamycin-sensitive signalling pathway. EMBO J, 15(9): 2291–2297

[98] Reid J M, Walden C A, Qin R, Ziegler K L, Haslam J L, Rajewski R A, Warndahl R, Fitting C L, Boring D, Szabo E, Crowell J, Perloff M, Jong L, Bauer B A, Mandrekar S J, Ames M M, Limburg P J, and the Cancer Prevention Network (2011). Phase 0 clinical chemoprevention trial of the Akt inhibitor SR13668. Cancer Prev Res (Phila), 4(3): 347–353

[99] Reif K, Burgering B M, Cantrell D A (1997). Phosphatidylinositol 3-kinase links the interleukin-2 receptor to protein kinase B and p70 S6 kinase. J Biol Chem, 272(22): 14426–14433

[100] Remy I, Montmarquette A, Michnick S W (2004). PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol, 6(4): 358–365

[101] Reneer M C, Estes D J, Velez-Ortega A C, Norris A, Mayer M, Marti F (2011). Peripherally induced human regulatory T cells uncouple Kv1.3 activation from TCR-associated signaling. Eur J Immunol, 41(11):3170–3175

[102] Rengarajan J, Tang B, Glimcher L H (2002). NFATc2 and NFATc3 regulate T(H)2 differentiation and modulate TCR-responsiveness of naïve T(H)cells. Nat Immunol, 3(1): 48–54

[103] Rocher G, Letourneux C, Lenormand P, Porteu F (2007). Inhibition of B56-containing protein phosphatase 2As by the early response gene IEX-1 leads to control of Akt activity. J Biol Chem, 282(8): 5468–5477

[104] Roget K, Malissen M, Malbec O, Malissen B, Daëron M (2008). Non-T cell activation linker promotes mast cell survival by dampening the recruitment of SHIP1 by linker for activation of T cells. J Immunol, 180(6): 3689–3698

[105] Romashkova J A, Makarov S S (1999). NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature, 401(6748): 86–90

[106] Rondinone C M, Carvalho E, Wesslau C, Smith U P (1999). Impaired glucose transport and protein kinase B activation by insulin, but not okadaic acid, in adipocytes from subjects with Type II diabetes mellitus. Diabetologia, 42(7): 819–825

[107] Rong S B, Hu Y, Enyedy I, Powis G, Meuillet E J, Wu X, Wang R, Wang S, Kozikowski A P (2001). Molecular modeling studies of the Akt PH domain and its interaction with phosphoinositides. J Med Chem, 44(6): 898–908

[108] Salomon B, Bluestone J A (2001). Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol, 19(1): 225–252

[109] Sarbassov D D, Guertin D A, Ali S M, Sabatini D M (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science, 307(5712): 1098–1101

[110] Sasaki T, Irie-Sasaki J, Jones R G, Oliveira-dos-Santos A J, Stanford W L, Bolon B, Wakeham A, Itie A, Bouchard D, Kozieradzki I, Joza N, Mak T W, Ohashi P S, Suzuki A, Penninger J M (2000). Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science, 287(5455): 1040–1046

[111] Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight Z A, Cobb B S, Cantrell D, O’Connor E, Shokat K M, Fisher A G, Merkenschlager M (2008). T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA, 105(22): 7797–7802

[112] Shevach E M (2001). Certified professionals: CD4(+)CD25(+) suppressor T cells. J Exp Med, 193(11): F41–F46

[113] Shevach E M (2009). Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity, 30(5): 636–645

[114] Shimoke K, Chiba H (2001). Nerve growth factor prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced cell death via the Akt pathway by suppressing caspase-3-like activity using PC12 cells: relevance to therapeutical application for Parkinson’s disease. J Neurosci Res, 63(5): 402–409

[115] Sizemore N, Lerner N, Dombrowski N, Sakurai H, Stark G R (2002). Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF-kappa B) from Ikappa B and in phosphorylating the p65 subunit of NF-kappa B. J Biol Chem, 277(6): 3863–3869

[116] Song G, Ouyang G, Bao S (2005). The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med, 9(1): 59–71

[117] Song K, Wang H, Krebs T L, Danielpour D (2006). Novel roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 activation. EMBO J, 25(1): 58–69

[118] Staal S P (1987). Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci USA, 84(14): 5034–5037

[119] Staal S P, Hartley J W, Rowe W P (1977). Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma. Proc Natl Acad Sci USA, 74(7): 3065–3067

[120] Stahl M, Dijkers P F, Kops G J, Lens S M, Coffer P J, Burgering B M, Medema R H (2002). The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol, 168(10): 5024–5031

[121] Stambolic V, Suzuki A, de la Pompa J L, Brothers G M, Mirtsos C, Sasaki T, Ruland J, Penninger J M, Siderovski D P, Mak T W (1998). Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 95(1): 29–39

[122] Starr T K, Jameson S C, Hogquist K A (2003). Positive and negative selection of T cells. Annu Rev Immunol, 21(1): 139–176

[123] Suizu F, Hiramuki Y, Okumura F, Matsuda M, Okumura A J, Hirata N, Narita M, Kohno T, Yokota J, Bohgaki M, Obuse C, Hatakeyama S, Obata T, Noguchi M (2009). The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt. Dev Cell, 17(6): 800–810

[124] Tang Q, Bluestone J A (2008). The Foxp3⁺ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol, 9(3): 239–244

[125] Thomas C C, Deak M, Alessi D R, van Aalten D M (2002). High-resolution structure of the pleckstrin homology domain of protein kinase b/akt bound to phosphatidylinositol (3,4,5)-trisphosphate. Curr Biol, 12(14): 1256–1262

[126] Turinsky J, Damrau-Abney A (1998). Akt1 kinase and dynamics of insulin resistance in denervated muscles in vivo. Am J Physiol, 275(5 Pt 2): R1425–R1430

[127] Vignali D A, Collison L W, Workman C J (2008). How regulatory T cells work. Nat Rev Immunol, 8(7): 523–532

[128] Vlahos C J, Matter W F, Hui K Y, Brown R F (1994). A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem, 269(7): 5241–5248

[129] Vukmanovic-Stejic M, Zhang Y, Cook J E, Fletcher J M, McQuaid A, Masters J E, Rustin M H, Taams L S, Beverley P C, Macallan D C, Akbar A N (2006). Human CD4⁺ CD25^hi Foxp3⁺ regulatory T cells are derived by rapid turnover of memory populations in vivo. J Clin Invest, 116(9): 2423–2433

[130] Wan Q, Kozhaya L, ElHed A, Ramesh R, Carlson T J, Djuretic I M, Sundrud M S, Unutmaz D (2011). Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells. J Exp Med, 208(9): 1875–1887

[131] Wehrens E J, Mijnheer G, Duurland C L, Klein M, Meerding J, van Loosdregt J, de Jager W, Sawitzki B, Coffer PJ, Vastert B, Prakken B J, van Wijk F (2011). Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells. Blood, 118(13):3538–3548

[132] Werlen G, Hausmann B, Naeher D, Palmer E (2003). Signaling life and death in the thymus: timing is everything. Science, 299(5614): 1859–1863

[133] Wiesinger D, Gubler H U, Haefliger W, Hauser D (1974). Antiinflammatory activity of the new mould metabolite 11-desacetoxy-wortmannin and of some of its derivatives. Experientia, 30(2): 135–136

[134] Workman C J, Szymczak-Workman A L, Collison L W, Pillai M R, Vignali D A (2009). The development and function of regulatory T cells. Cell Mol Life Sci, 66(16): 2603–2622

[135] Xu L, Kitani A, Fuss I, Strober W (2007). Cutting edge: regulatory T cells induce CD4⁺CD25^-Foxp3^- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol, 178(11): 6725–6729

[136] Yang X O, Nurieva R, Martinez G J, Kang H S, Chung Y, Pappu B P, Shah B, Chang S H, Schluns K S, Watowich S S, Feng X H, Jetten A M, Dong C (2008). Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity, 29(1): 44–56

[137] Yang Z Z, Tschopp O, Baudry A, Dümmler B, Hynx D, Hemmings B A (2004). Physiological functions of protein kinase B/Akt. Biochem Soc Trans, 32(2): 350–354

[138] You S, Belghith M, Cobbold S, Alyanakian M A, Gouarin C, Barriot S, Garcia C, Waldmann H, Bach J F, Chatenoud L (2005). Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes, 54(5): 1415–1422

[139] Yung H W, Charnock-Jones D S, Burton G J (2011). Regulation of AKT phosphorylation at Ser473 and Thr308 by endoplasmic reticulum stress modulates substrate specificity in a severity dependent manner. PLoS ONE, 6(3): e17894

[140] Zhou L, Lopes J E, Chong M M, Ivanov I I, Min R, Victora G D, Shen Y, Du J, Rubtsov Y P, Rudensky A Y, Ziegler S F, Littman D R (2008). TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature, 453(7192): 236–240

[141] Ziegler S F (2006). FOXP3: of mice and men. Annu Rev Immunol, 24(1): 209–226

Acknowledgments

We thank M. Moliner for assistance with graphics. This work was partially supported by NIH Grant Numbers R03AR052904-02 from the NIAMS and 2P20 RR020171 from the NCRR to F.M. The authors declare no financial or commercial conflict of interest.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg