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PI3Ks in Lymphocyte Signaling and Development

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Phosphoinositide 3-kinase in Health and Disease

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 346))

Abstract

Lymphocyte development and function are regulated by tyrosine kinase and G-protein coupled receptors. Each of these classes of receptors activates phosphoinositide 3-kinase (PI3K). In this chapter, we summarize current understanding of how PI3K contributes to key aspects of the adaptive immune system.

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Abbreviations

APC:

Antigen presenting cell

BAFF:

B-cell activation factor of the tumor necrosis factor family

BCAP:

B cell adaptor protein

BcR:

B-cell antigen receptor

DC:

Dendritic cell

dko:

Double knockout

DN:

Double negative

DP:

Double positive

FO:

Follicular

Foxo:

Forkhead box subgroup O

GEF:

Guanine nucleotide exchange factor

GPCR:

G-protein coupled receptor

IFN-γ:

Interferon-gamma

IL-10:

Interleukin-10

IL-2:

Interleukin-2

IL-4:

Interleukin-4

IL-7:

Interleukin-7

KLF2:

Krüppel-like factor-2

LPS:

Lipopolysaccharide

MHC:

Major histocompatibility complex

mTOR:

Mammalian target of rapamycin

mTORC1:

mTOR complex-1

MZ:

Marginal zone

NK:

Natural killer

PI3K:

Phosphoinositide 3-kinase

PIP2 :

Phosphatidylinositol-4,5-bisphosphate

PIP3 :

Phosphatidylinositol-3,4,5-trisphosphate

PKCβ:

Protein kinase C-beta

PKCθ:

Protein kinase C-theta

PLCγ:

Phospholipase C-gamma

pMHC:

Peptide-MHC

RAG:

Recombination-activating gene

S1P:

Sphingosine-1-phosphate

SH2:

Src homology-2

SLP-65:

SH2 domain containing protein of 65 kDa

TcR:

T-cell antigen receptor

Th1:

T helper type-1

Th2:

T helper type-2

TLR:

Toll-like receptor

Tregs:

Regulatory T cells

References

  • Aiba Y, Kameyama M, Yamazaki T, Tedder TF, Kurosaki T (2008) Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase. Blood 111:1497–1503

    PubMed  CAS  Google Scholar 

  • Al-Alwan MM, Okkenhaug K, Vanhaesebroeck B, Hayflick JS, Marshall AJ (2007) Requirement for phosphoinositide 3-kinase p110delta signaling in B cell antigen receptor-mediated antigen presentation. J Immunol 178:2328–2335

    PubMed  CAS  Google Scholar 

  • Alcazar I, Marques M, Kumar A, Hirsch E, Wymann M, Carrera AC, Barber DF (2007) Phosphoinositide 3-kinase gamma participates in T cell receptor-induced T cell activation. J Exp Med 204:2977–2987

    PubMed  CAS  Google Scholar 

  • Alcazar I, Cortes I, Zaballos A, Hernandez C, Fruman DA, Barber DF, Carrera AC (2009) p85beta phosphoinositide 3-kinase regulates CD28 coreceptor function. Blood 113:3198–3208

    PubMed  CAS  Google Scholar 

  • Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R, Bruce I, Walker C, Sawyer C, Okkenhaug K, Finan P, Vanhaesebroeck B (2004) Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature 431:1007–1011

    PubMed  CAS  Google Scholar 

  • Ali K, Camps M, Pearce WP, Ji H, Ruckle T, Kuehn N, Pasquali C, Chabert C, Rommel C, Vanhaesebroeck B (2008) Isoform-specific functions of phosphoinositide 3-kinases: p110 delta but not p110 gamma promotes optimal allergic responses in vivo. J Immunol 180:2538–2544

    PubMed  CAS  Google Scholar 

  • Amin RH, Schlissel MS (2008) Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nat Immunol 9:613–622

    PubMed  CAS  Google Scholar 

  • Asperti-Boursin F, Real E, Bismuth G, Trautmann A, Donnadieu E (2007) CCR7 ligands control basal T cell motility within lymph node slices in a phosphoinositide 3-kinase-independent manner. J Exp Med 204:1167–1179

    PubMed  CAS  Google Scholar 

  • Bajenoff M, Egen JG, Koo LY, Laugier JP, Brau F, Glaichenhaus N, Germain RN (2006) Stromal cell networks regulate lymphocyte entry, migration, and territoriality in lymph nodes. Immunity 25:989–1001

    PubMed  CAS  Google Scholar 

  • Barber DF, Bartolome A, Hernandez C, Flores JM, Redondo C, Fernandez-Arias C, Camps M, Ruckle T, Schwarz MK, Rodriguez S, Martinez AC, Balomenos D, Rommel C, Carrera AC (2005) PI3Kgamma inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nat Med 11:933–935

    PubMed  CAS  Google Scholar 

  • Barber DF, Bartolome A, Hernandez C, Flores JM, Fernandez-Arias C, Rodriguez-Borlado L, Hirsch E, Wymann M, Balomenos D, Carrera AC (2006) Class IB-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates IA-PI3K-induced systemic lupus but not T cell invasion. J Immunol 176:589–593

    PubMed  CAS  Google Scholar 

  • Bensinger SJ, Walsh PT, Zhang J, Carroll M, Parsons R, Rathmell JC, Thompson CB, Burchill MA, Farrar MA, Turka LA (2004) Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 172:5287–5296

    PubMed  CAS  Google Scholar 

  • Bilancio A, Okkenhaug K, Camps M, Emery JL, Ruckle T, Rommel C, Vanhaesebroeck B (2006) Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells. Blood 107:642–650

    PubMed  CAS  Google Scholar 

  • Bluestone JA, St Clair EW, Turka LA (2006) CTLA4Ig: bridging the basic immunology with clinical application. Immunity 24:233–238

    PubMed  CAS  Google Scholar 

  • Brauweiler A, Tamir I, Dal Porto J, Benschop RJ, Helgason CD, Humphries RK, Freed JH, Cambier JC (2000) Differential regulation of B cell development, activation, and death by the src homology 2 domain-containing 5′ inositol phosphatase (SHIP). J Exp Med 191:1545–1554

    PubMed  CAS  Google Scholar 

  • Browne CD, Del Nagro CJ, Cato MH, Dengler HS, Rickert RC (2009) Suppression of phosphatidylinositol 3,4,5-trisphosphate production is a key determinant of B cell anergy. Immunity 31:749–760

    PubMed  CAS  Google Scholar 

  • Bruyns E, Marie-Cardine A, Kirchgessner H, Sagolla K, Shevchenko A, Mann M, Autschbach F, Bensussan A, Meuer S, Schraven B (1998) T cell receptor (TCR) interacting molecule (TRIM), a novel disulfide-linked dimer associated with the TCR-CD3-zeta complex, recruits intracellular signaling proteins to the plasma membrane. J Exp Med 188:561–575

    PubMed  CAS  Google Scholar 

  • Burr JS, Savage ND, Messah GE, Kimzey SL, Shaw AS, Arch RH, Green JM (2001) Cutting edge: distinct motifs within CD28 regulate T cell proliferation and induction of Bcl-XL. J Immunol 166:5331–5335

    PubMed  CAS  Google Scholar 

  • Camps M, Ruckle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Francon B, Martin T, Gretener D, Perrin D, Leroy D, Vitte PA, Hirsch E, Wymann MP, Cirillo R, Schwarz MK, Rommel C (2005) Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med 11:936–943

    PubMed  CAS  Google Scholar 

  • Ciofani M, Zuniga-Pflucker JC (2005) Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat Immunol 6:881–888

    PubMed  CAS  Google Scholar 

  • Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, Humphries LA, Rawlings D, Reynolds H, Vigorito E, Turner M (2002) A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med 196:753–763

    PubMed  CAS  Google Scholar 

  • Coffer PJ, Burgering BM (2004) Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 4:889–899

    PubMed  CAS  Google Scholar 

  • Crabbe T, Welham MJ, Ward SG (2007) The PI3K inhibitor arsenal: choose your weapon! Trends Biochem Sci 32:450–456

    PubMed  CAS  Google Scholar 

  • Crellin NK, Garcia RV, Levings MK (2007) Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells. Blood 109:2014–2022

    PubMed  CAS  Google Scholar 

  • Deane JA, Trifilo MJ, Yballe CM, Choi S, Lane TE, Fruman DA (2004) Enhanced T cell proliferation in mice lacking the p85beta subunit of phosphoinositide 3-kinase. J Immunol 172:6615–6625

    PubMed  CAS  Google Scholar 

  • Deane JA, Kharas MG, Oak JS, Stiles LN, Luo J, Moore TI, Ji H, Rommel C, Cantley LC, Lane TE, Fruman DA (2007) T cell function is partially maintained in the absence of class IA phosphoinositide 3-kinase signaling. Blood 109:2894–2902

    PubMed  CAS  Google Scholar 

  • Delgado P, Cubelos B, Calleja E, Martinez-Martin N, Cipres A, Merida I, Bellas C, Bustelo XR, Alarcon B (2009) Essential function for the GTPase TC21 in homeostatic antigen receptor signaling. Nat Immunol 10:880–888

    PubMed  CAS  Google Scholar 

  • Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:832–844

    PubMed  CAS  Google Scholar 

  • Dengler HS, Baracho GV, Omori SA, Bruckner S, Arden KC, Castrillon DH, DePinho RA, Rickert RC (2008) Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nat Immunol 9:1388–1398

    PubMed  CAS  Google Scholar 

  • Depoil D, Fleire S, Treanor BL, Weber M, Harwood NE, Marchbank KL, Tybulewicz VL, Batista FD (2008) CD19 is essential for B cell activation by promoting B cell receptor-antigen microcluster formation in response to membrane-bound ligand. Nat Immunol 9:63–72

    PubMed  CAS  Google Scholar 

  • Diehn M, Alizadeh AA, Rando OJ, Liu CL, Stankunas K, Botstein D, Crabtree GR, Brown PO (2002) Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc Natl Acad Sci USA 99:11796–11801

    PubMed  CAS  Google Scholar 

  • Doi T, Obayashi K, Kadowaki T, Fujii H, Koyasu S (2008) PI3K is a negative regulator of IgE production. Int Immunol 20:499–508

    PubMed  CAS  Google Scholar 

  • Donahue AC, Fruman DA (2007) Distinct signaling mechanisms activate the target of rapamycin in response to different B-cell stimuli. Eur J Immunol 37:2923–2936

    PubMed  CAS  Google Scholar 

  • Donahue AC, Hess KL, Ng KL, Fruman DA (2004) Altered splenic B cell subset development in mice lacking phosphoinositide 3-kinase p85alpha. Int Immunol 16:1789–1798

    PubMed  CAS  Google Scholar 

  • Dong H, Zhu G, Tamada K, Chen L (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5:1365–1369

    PubMed  CAS  Google Scholar 

  • Doughty CA, Bleiman BF, Wagner DJ, Dufort FJ, Mataraza JM, Roberts MF, Chiles TC (2006) Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. Blood 107:4458–4465

    PubMed  CAS  Google Scholar 

  • Edwards JC, Leandro MJ, Cambridge G (2004) B lymphocyte depletion therapy with rituximab in rheumatoid arthritis. Rheum Dis Clin North Am 30:393–403, viii

    PubMed  CAS  Google Scholar 

  • Fabre S, Lang V, Harriague J, Jobart A, Unterman TG, Trautmann A, Bismuth G (2005) Stable activation of phosphatidylinositol 3-kinase in the T cell immunological synapse stimulates Akt signaling to FoxO1 nuclear exclusion and cell growth control. J Immunol 174:4161–4171

    PubMed  CAS  Google Scholar 

  • Fabre S, Carrette F, Chen J, Lang V, Semichon M, Denoyelle C, Lazar V, Cagnard N, Dubart-Kupperschmitt A, Mangeney M, Fruman DA, Bismuth G (2008) FOXO1 regulates L-selectin and a network of human T cell homing molecules downstream of phosphatidylinositol 3-kinase. J Immunol 181:2980–2989

    PubMed  CAS  Google Scholar 

  • Fayard E, Gill J, Paolino M, Hynx D, Hollander GA, Hemmings BA (2007) Deletion of PKBalpha/Akt1 affects thymic development. PLoS One 2:e992

    PubMed  Google Scholar 

  • Feldmann M, Maini SR (2008) Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol Rev 223:7–19

    PubMed  CAS  Google Scholar 

  • Finlay DK, Sinclair LV, Feijoo C, Waugh CM, Hagenbeek TJ, Spits H, Cantrell DA (2009) Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes. J Exp Med 206:2441–2454

    PubMed  CAS  Google Scholar 

  • Floto RA, Clatworthy MR, Heilbronn KR, Rosner DR, MacAry PA, Rankin A, Lehner PJ, Ouwehand WH, Allen JM, Watkins NA, Smith KG (2005) Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts. Nat Med 11:1056–1058

    PubMed  CAS  Google Scholar 

  • Fos C, Salles A, Lang V, Carrette F, Audebert S, Pastor S, Ghiotto M, Olive D, Bismuth G, Nunes JA (2008) ICOS ligation recruits the p50alpha PI3K regulatory subunit to the immunological synapse. J Immunol 181:1969–1977

    PubMed  CAS  Google Scholar 

  • Fox CJ, Hammerman PS, Thompson CB (2005) The Pim kinases control rapamycin-resistant T cell survival and activation. J Exp Med 201:259–266

    PubMed  CAS  Google Scholar 

  • Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB (2002) The CD28 signaling pathway regulates glucose metabolism. Immunity 16:769–777

    PubMed  CAS  Google Scholar 

  • Fruman DA, Bismuth G (2009) Fine tuning the immune response with PI3K. Immunol Rev 228:253–272

    PubMed  CAS  Google Scholar 

  • Fruman DA, Snapper SB, Yballe CM, Davidson L, Yu JY, Alt FW, Cantley LC (1999) Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha. Science 283:393–397

    PubMed  CAS  Google Scholar 

  • Fruman DA, Satterthwaite AB, Witte ON (2000) Xid-like phenotypes: a B cell signalosome takes shape. Immunity 13:1–3

    PubMed  CAS  Google Scholar 

  • Fukao T, Tanabe M, Terauchi Y, Ota T, Matsuda S, Asano T, Kadowaki T, Takeuchi T, Koyasu S (2002) PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat Immunol 3:875–881

    PubMed  CAS  Google Scholar 

  • Garcon F, Patton DT, Emery JL, Hirsch E, Rottapel R, Sasaki T, Okkenhaug K (2008) CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer. Blood 111:1464–1471

    PubMed  CAS  Google Scholar 

  • Gigoux M, Shang J, Pak Y, Xu M, Choe J, Mak TW, Suh WK (2009) Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. Proc Natl Acad Sci USA 106:20371–20376

    PubMed  CAS  Google Scholar 

  • Gollmer K, Asperti-Boursin F, Tanaka Y, Okkenhaug K, Vanhaesebroeck B, Peterson JR, Fukui Y, Donnadieu E, Stein JV (2009) CCL21 mediates CD4+ T cell costimulation via a DOCK2/Rac-dependent pathway. Blood 114:580–588

    PubMed  CAS  Google Scholar 

  • Gruber T, Freeley M, Thuille N, Heit I, Shaw S, Long A, Baier G (2006) Comment on “PDK1 nucleates T cell receptor-induced signaling complex for NF-kappaB activation”. Science 312:55, author reply 55

    PubMed  CAS  Google Scholar 

  • Guo H, Samarakoon A, Vanhaesebroeck B, Malarkannan S (2008) The p110 delta of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation. J Exp Med 205:2419–2435

    PubMed  CAS  Google Scholar 

  • Hagenbeek TJ, Naspetti M, Malergue F, Garcon F, Nunes JA, Cleutjens KB, 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 200:883–894

    PubMed  CAS  Google Scholar 

  • Hardy RR, Kincade PW, Dorshkind K (2007) The protean nature of cells in the B lymphocyte lineage. Immunity 26:703–714

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Henley T, Kovesdi D, Turner M (2008) B-cell responses to B-cell activation factor of the TNF family (BAFF) are impaired in the absence of PI3K delta. Eur J Immunol 38:3543–3548

    PubMed  CAS  Google Scholar 

  • Herzog S, Hug E, Meixlsperger S, Paik JH, DePinho RA, Reth M, Jumaa H (2008) SLP-65 regulates immunoglobulin light chain gene recombination through the PI(3)K-PKB-Foxo pathway. Nat Immunol 9:623–631

    PubMed  CAS  Google Scholar 

  • Herzog S, Reth M, Jumaa H (2009) Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling. Nat Rev Immunol 9:195–205

    PubMed  CAS  Google Scholar 

  • Hess KL, Donahue AC, Ng KL, Moore TI, Oak J, Fruman DA (2004) Frontline: the p85alpha isoform of phosphoinositide 3-kinase is essential for a subset of B cell receptor-initiated signaling responses. Eur J Immunol 34:2968–2976

    PubMed  CAS  Google Scholar 

  • Hinton HJ, Alessi DR, Cantrell DA (2004) The serine kinase phosphoinositide-dependent kinase 1 (PDK1) regulates T cell development. Nat Immunol 5:539–545

    PubMed  CAS  Google Scholar 

  • Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, Silengo L, Sozzani S, Mantovani A, Altruda F, Wymann MP (2000) Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 287:1049–1053

    PubMed  CAS  Google Scholar 

  • Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397:263–266

    PubMed  CAS  Google Scholar 

  • Inabe K, Ishiai M, Scharenberg AM, Freshney N, Downward J, Kurosaki T (2002) Vav3 modulates B cell receptor responses by regulating phosphoinositide 3-kinase activation. J Exp Med 195:189–200

    PubMed  CAS  Google Scholar 

  • Izcue A, Coombes JL, Powrie F (2009) Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27:313–338

    PubMed  CAS  Google Scholar 

  • Jacobs MD, Black J, Futer O, Swenson L, Hare B, Fleming M, Saxena K (2005) Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002. J Biol Chem 280:13728–13734

    PubMed  CAS  Google Scholar 

  • Janas ML, Hodson D, Stamataki Z, Hill S, Welch K, Gambardella L, Trotman LC, Pandolfi PP, Vigorito E, Turner M (2008) The effect of deleting p110delta on the phenotype and function of PTEN-deficient B cells. J Immunol 180:739–746

    PubMed  CAS  Google Scholar 

  • Janas ML, Varano G, Gudmundsson K, Noda M, Nagasawa T, Turner M (2010) Thymic development beyond beta-selection requires phosphatidylinositol 3-kinase activation by CXCR4. J Exp Med 207(247–261):S241–S242

    Google Scholar 

  • Jarmin SJ, David R, Ma L, Chai JG, Dewchand H, Takesono A, Ridley AJ, Okkenhaug K, Marelli-Berg FM (2008) T cell receptor-induced phosphoinositide-3-kinase p110delta activity is required for T cell localization to antigenic tissue in mice. J Clin Invest 118:1154–1164

    PubMed  CAS  Google Scholar 

  • Ji H, Rintelen F, Waltzinger C, Bertschy Meier D, Bilancio A, Pearce W, Hirsch E, Wymann MP, Ruckle T, Camps M, Vanhaesebroeck B, Okkenhaug K, Rommel C (2007) Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation. Blood 110:2940–2947

    PubMed  CAS  Google Scholar 

  • Jimenez C, Portela RA, Mellado M, Rodriguez-Frade JM, Collard J, Serrano A, Martinez AC, Avila J, Carrera AC (2000) Role of the PI3K regulatory subunit in the control of actin organization and cell migration. J Cell Biol 151:249–262

    PubMed  CAS  Google Scholar 

  • Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, Carpino N, Wang D, Ihle JN (2002) Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol 22:8580–8591

    PubMed  CAS  Google Scholar 

  • Juntilla MM, Wofford JA, Birnbaum MJ, Rathmell JC, Koretzky GA (2007) Akt1 and Akt2 are required for alphabeta thymocyte survival and differentiation. Proc Natl Acad Sci USA 104:12105–12110

    PubMed  CAS  Google Scholar 

  • Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A (2002) Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription. Mol Cell Biol 22:5962–5974

    PubMed  CAS  Google Scholar 

  • Kelly AP, Finlay DK, Hinton HJ, Clarke RG, Fiorini E, Radtke F, Cantrell DA (2007) Notch-induced T cell development requires phosphoinositide-dependent kinase 1. EMBO J 26:3441–3450

    PubMed  CAS  Google Scholar 

  • Kerdiles YM, Beisner DR, Tinoco R, Dejean AS, Castrillon DH, DePinho RA, Hedrick SM (2009) Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol 10:176–184

    PubMed  CAS  Google Scholar 

  • Kim JM, Rasmussen JP, Rudensky AY (2007a) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8:191–197

    PubMed  CAS  Google Scholar 

  • Kim N, Saudemont A, Webb L, Camps M, Ruckle T, Hirsch E, Turner M, Colucci F (2007b) The p110delta catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion. Blood 110:3202–3208

    PubMed  CAS  Google Scholar 

  • Kishimoto H, Ohteki T, Yajima N, Kawahara K, Natsui M, Kawarasaki S, Hamada K, Horie Y, Kubo Y, Arase S, Taniguchi M, Vanhaesebroeck B, Mak TW, Nakano T, Koyasu S, Sasaki T, Suzuki A (2007) The Pten/PI3K pathway governs the homeostasis of Valpha14iNKT cells. Blood 109:3316–3324

    PubMed  CAS  Google Scholar 

  • Kolsch U, Arndt B, Reinhold D, Lindquist JA, Juling N, Kliche S, Pfeffer K, Bruyns E, Schraven B, Simeoni L (2006) Normal T-cell development and immune functions in TRIM-deficient mice. Mol Cell Biol 26:3639–3648

    PubMed  Google Scholar 

  • Kumar A, Humphreys TD, Kremer KN, Bramati PS, Bradfield L, Edgar CE, Hedin KE (2006) CXCR4 physically associates with the T cell receptor to signal in T cells. Immunity 25:213–224

    PubMed  CAS  Google Scholar 

  • Lee KY, D’Acquisto F, Hayden MS, Shim JH, Ghosh S (2005) PDK1 nucleates T cell receptor-induced signaling complex for NF-kappaB activation. Science 308:114–118

    PubMed  CAS  Google Scholar 

  • Lee KS, Lee HK, Hayflick JS, Lee YC, Puri KD (2006) Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. FASEB J 20:455–465

    PubMed  CAS  Google Scholar 

  • Li MO, Flavell RA (2008) TGF-beta: a master of all T cell trades. Cell 134:392–404

    PubMed  CAS  Google Scholar 

  • Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D (2000) Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractant-mediated signal transduction. Science 287:1046–1049

    PubMed  CAS  Google Scholar 

  • Lin L, Hron JD, Peng SL (2004) Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. Immunity 21:203–213

    PubMed  CAS  Google Scholar 

  • Link A, Vogt TK, Favre S, Britschgi MR, Acha-Orbea H, Hinz B, Cyster JG, Luther SA (2007) Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat Immunol 8:1255–1265

    PubMed  CAS  Google Scholar 

  • Liu D, Zhang T, Marshall AJ, Okkenhaug K, Vanhaesebroeck B, Uzonna JE (2009) The p110delta isoform of phosphatidylinositol 3-kinase controls susceptibility to Leishmania major by regulating expansion and tissue homing of regulatory T cells. J Immunol 183:1921–1933

    PubMed  CAS  Google Scholar 

  • Llorian M, Stamataki Z, Hill S, Turner M, Martensson IL (2007) The PI3K p110delta is required for down-regulation of RAG expression in immature B cells. J Immunol 178:1981–1985

    PubMed  CAS  Google Scholar 

  • Locke NR, Patterson SJ, Hamilton MJ, Sly LM, Krystal G, Levings MK (2009) SHIP regulates the reciprocal development of T regulatory and Th17 cells. J Immunol 183:975–983

    PubMed  CAS  Google Scholar 

  • Mao C, Tili EG, Dose M, Haks MC, Bear SE, Maroulakou I, Horie K, Gaitanaris GA, Fidanza V, Ludwig T, Wiest DL, Gounari F, Tsichlis PN (2007) Unequal contribution of Akt isoforms in the double-negative to double-positive thymocyte transition. J Immunol 178:5443–5453

    PubMed  CAS  Google Scholar 

  • Martin AL, Schwartz MD, Jameson SC, Shimizu Y (2008) Selective regulation of CD8 effector T cell migration by the p110 gamma isoform of phosphatidylinositol 3-kinase. J Immunol 180:2081–2088

    PubMed  CAS  Google Scholar 

  • Matheu MP, Deane JA, Parker I, Fruman DA, Cahalan MD (2007) Class IA phosphoinositide 3-kinase modulates basal lymphocyte motility in the lymph node. J Immunol 179:2261–2269

    PubMed  CAS  Google Scholar 

  • Mirenda V, Jarmin SJ, David R, Dyson J, Scott D, Gu Y, Lechler RI, Okkenhaug K, Marelli-Berg FM (2007) Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28. Blood 109:2968–2977

    PubMed  CAS  Google Scholar 

  • Molon B, Gri G, Bettella M, Gomez-Mouton C, Lanzavecchia A, Martinez AC, Manes S, Viola A (2005) T cell costimulation by chemokine receptors. Nat Immunol 6:465–471

    PubMed  CAS  Google Scholar 

  • Narayan P, Holt B, Tosti R, Kane LP (2006) CARMA1 is required for Akt-mediated NF-kappaB activation in T cells. Mol Cell Biol 26:2327–2336

    PubMed  CAS  Google Scholar 

  • Nashed BF, Zhang T, Al-Alwan M, Srinivasan G, Halayko AJ, Okkenhaug K, Vanhaesebroeck B, Hayglass KT, Marshall AJ (2007) Role of the phosphoinositide 3-kinase p110delta in generation of type 2 cytokine responses and allergic airway inflammation. Eur J Immunol 37:416–424

    PubMed  CAS  Google Scholar 

  • Nombela-Arrieta C, Lacalle RA, Montoya MC, Kunisaki Y, Megias D, Marques M, Carrera AC, Manes S, Fukui Y, Martinez AC, Stein JV (2004) Differential requirements for DOCK2 and phosphoinositide-3-kinase gamma during T and B lymphocyte homing. Immunity 21:429–441

    PubMed  CAS  Google Scholar 

  • Nombela-Arrieta C, Mempel TR, Soriano SF, Mazo I, Wymann MP, Hirsch E, Martinez AC, Fukui Y, von Andrian UH, Stein JV (2007) A central role for DOCK2 during interstitial lymphocyte motility and sphingosine-1-phosphate-mediated egress. J Exp Med 204:497–510

    PubMed  CAS  Google Scholar 

  • Oak JS, Deane JA, Kharas MG, Luo J, Lane TE, Cantley LC, Fruman DA (2006) Sjogren’s syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase. Proc Natl Acad Sci USA 103:16882–16887

    PubMed  CAS  Google Scholar 

  • Oak JS, Chen J, Peralta RQ, Deane JA, Fruman DA (2009) The p85beta regulatory subunit of phosphoinositide 3-kinase has unique and redundant functions in B cells. Autoimmunity 442:447–458

    Google Scholar 

  • Okkenhaug K, Wu L, Garza KM, La Rose J, Khoo W, Odermatt B, Mak TW, Ohashi PS, Rottapel R (2001) A point mutation in CD28 distinguishes proliferative signals from survival signals. Nat Immunol 2:325–332

    PubMed  CAS  Google Scholar 

  • Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297:1031–1034

    PubMed  CAS  Google Scholar 

  • Okkenhaug K, Patton DT, Bilancio A, Garcon F, Rowan WC, Vanhaesebroeck B (2006) The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol 177:5122–5128

    PubMed  CAS  Google Scholar 

  • Okkenhaug K, Ali K, Vanhaesebroeck B (2007) Antigen receptor signalling: a distinctive role for the p110delta isoform of PI3K. Trends Immunol 28:80–87

    PubMed  CAS  Google Scholar 

  • Omori SA, Cato MH, Anzelon-Mills A, Puri KD, Shapiro-Shelef M, Calame K, Rickert RC (2006) Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity 25:545–557

    PubMed  CAS  Google Scholar 

  • Ouyang W, Beckett O, Flavell RA, Li MO (2009) An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity 30:358–371

    PubMed  CAS  Google Scholar 

  • Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins SL, Bhagat G, Agarwal AM, Basso G, Castillo M, Nagase S, Cordon-Cardo C, Parsons R, Zuniga-Pflucker JC, Dominguez M, Ferrando AA (2007) Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13:1203–1210

    PubMed  CAS  Google Scholar 

  • Park SG, Schulze-Luehrman J, Hayden MS, Hashimoto N, Ogawa W, Kasuga M, Ghosh S (2009) The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-kappaB and activate T cells. Nat Immunol 10:158–166

    PubMed  CAS  Google Scholar 

  • Parry RV, Rumbley CA, Vandenberghe LH, June CH, Riley JL (2003) CD28 and inducible costimulatory protein Src homology 2 binding domains show distinct regulation of phosphatidylinositol 3-kinase, Bcl-xL, and IL-2 expression in primary human CD4 T lymphocytes. J Immunol 171:166–174

    PubMed  CAS  Google Scholar 

  • Parry RV, Harris SJ, Ward SG (2010) Fine tuning T lymphocytes: a role for the lipid phosphatase SHIP-1. Biochim Biophys Acta 1804:592–597

    PubMed  CAS  Google Scholar 

  • Patton DT, Garden OA, Pearce WP, Clough LE, Monk CR, Leung E, Rowan WC, Sancho S, Walker LS, Vanhaesebroeck B, Okkenhaug K (2006) Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J Immunol 177:6598–6602

    PubMed  CAS  Google Scholar 

  • Phee H, Rodgers W, Coggeshall KM (2001) Visualization of negative signaling in B cells by quantitative confocal microscopy. Mol Cell Biol 21:8615–8625

    PubMed  CAS  Google Scholar 

  • Pierau M, Engelmann S, Reinhold D, Lapp T, Schraven B, Bommhardt UH (2009) Protein kinase B/Akt signals impair Th17 differentiation and support natural regulatory T cell function and induced regulatory T cell formation. J Immunol 183:6124–6134

    PubMed  CAS  Google Scholar 

  • Randis TM, Puri KD, Zhou H, Diacovo TG (2008) Role of PI3Kdelta and PI3Kgamma in inflammatory arthritis and tissue localization of neutrophils. Eur J Immunol 38:1215–1224

    PubMed  CAS  Google Scholar 

  • Reif K, Okkenhaug K, Sasaki T, Penninger JM, Vanhaesebroeck B, Cyster JG (2004) Cutting edge: differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing. J Immunol 173:2236–2240

    PubMed  CAS  Google Scholar 

  • Riley JL, Mao M, Kobayashi S, Biery M, Burchard J, Cavet G, Gregson BP, June CH, Linsley PS (2002) Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc Natl Acad Sci USA 99:11790–11795

    PubMed  CAS  Google Scholar 

  • Roberts TM, Ilić N (2010) Comparing the roles of the p110a and p110b isoforms of PI3K in signaling and cancer. Curr Top Microbiol Immunol doi 10.1007/82_2010_63

    PubMed  Google Scholar 

  • Rodriguez-Borlado L, Barber DF, Hernandez C, Rodriguez-Marcos MA, Sanchez A, Hirsch E, Wymann M, Martinez AC, Carrera AC (2003) Phosphatidylinositol 3-kinase regulates the CD4/CD8 T cell differentiation ratio. J Immunol 170:4475–4482

    PubMed  CAS  Google Scholar 

  • Rommel C, Camps M, Ji H (2007) PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 7:191–201

    PubMed  CAS  Google Scholar 

  • Ruckle T, Schwarz MK, Rommel C (2006) PI3Kgamma inhibition: towards an ‘aspirin of the 21st century’? Nat Rev Drug Discov 5:903–918

    PubMed  Google Scholar 

  • Rudd CE, Schneider H (2003) Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol 3:544–556

    PubMed  CAS  Google Scholar 

  • Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787

    PubMed  CAS  Google Scholar 

  • Sanchez-Lockhart M, Marin E, Graf B, Abe R, Harada Y, Sedwick CE, Miller J (2004) Cutting edge: CD28-mediated transcriptional and posttranscriptional regulation of IL-2 expression are controlled through different signaling pathways. J Immunol 173:7120–7124

    PubMed  CAS  Google Scholar 

  • Sanchez-Lockhart M, Graf B, Miller J (2008) Signals and sequences that control CD28 localization to the central region of the immunological synapse. J Immunol 181:7639–7648

    PubMed  CAS  Google Scholar 

  • Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, Wakeham A, Itie A, Bouchard D, Kozieradzki I, Joza N, Mak TW, Ohashi PS, Suzuki A, Penninger JM (2000) Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science 287:1040–1046

    PubMed  CAS  Google Scholar 

  • Saudemont A, Garcon F, Yadi H, Roche-Molina M, Kim N, Segonds-Pichon A, Martin-Fontecha A, Okkenhaug K, Colucci F (2009) p110gamma and p110delta isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease. Proc Natl Acad Sci USA 106:5795–5800

    PubMed  CAS  Google Scholar 

  • Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O’Connor E, Shokat KM, Fisher AG, Merkenschlager M (2008) T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA 105:7797–7802

    PubMed  CAS  Google Scholar 

  • Saveliev A, Vanes L, Ksionda O, Rapley J, Smerdon SJ, Rittinger K, Tybulewicz VLJ (2009) Function of the nucleotide exchange activity of vav1 in T cell development and activation. Sci Signal 2:ra83

    PubMed  Google Scholar 

  • Schulze-Luehrmann J, Ghosh S (2006) Antigen-receptor signaling to nuclear factor kappa B. Immunity 25:701–715

    PubMed  CAS  Google Scholar 

  • Sebzda E, Zou Z, Lee JS, Wang T, Kahn ML (2008) Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns. Nat Immunol 9:292–300

    PubMed  CAS  Google Scholar 

  • Shiroki F, Matsuda S, Doi T, Fujiwara M, Mochizuki Y, Kadowaki T, Suzuki H, Koyasu S (2007) The p85alpha regulatory subunit of class IA phosphoinositide 3-kinase regulates beta-selection in thymocyte development. J Immunol 178:1349–1356

    PubMed  CAS  Google Scholar 

  • Sinclair LV, Finlay D, Feijoo C, Cornish GH, Gray A, Ager A, Okkenhaug K, Hagenbeek TJ, Spits H, Cantrell DA (2008) Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat Immunol 9:513–521

    PubMed  CAS  Google Scholar 

  • Sommers CL, Gurson JM, Surana R, Barda-Saad M, Lee J, Kishor A, Li W, Gasser AJ, Barr VA, Miyaji M, Love PE, Samelson LE (2008) Bam32: a novel mediator of Erk activation in T cells. Int Immunol 20:811–818

    PubMed  CAS  Google Scholar 

  • Soond DR, Bjorgo E, Moltu K, Dale VQ, Patton DT, Torgersen KM, Galleway F, Twomey B, Clark J, Gaston JH, Tasken K, Bunyard P, Okkenhaug K (2010) PI3K p110{delta} regulates T cell cytokine production during primary and secondary immune responses in mice and humans. Blood 115:2203–2213

    PubMed  CAS  Google Scholar 

  • Srinivasan L, Sasaki Y, Calado DP, Zhang B, Paik JH, DePinho RA, Kutok JL, Kearney JF, Otipoby KL, Rajewsky K (2009) PI3 kinase signals BCR-dependent mature B cell survival. Cell 139:573–586

    PubMed  CAS  Google Scholar 

  • Sriskantharajah S, Belich MP, Papoutsopoulou S, Janzen J, Tybulewicz V, Seddon B, Ley SC (2009) Proteolysis of NF-kappaB1 p105 is essential for T cell antigen receptor-induced proliferation. Nat Immunol 10:38–47

    PubMed  CAS  Google Scholar 

  • Suzuki H, Terauchi Y, Fujiwara M, Aizawa S, Yazaki Y, Kadowaki T, Koyasu S (1999) Xid-like immunodeficiency in mice with disruption of the p85alpha subunit of phosphoinositide 3-kinase. Science 283:390–392

    PubMed  CAS  Google Scholar 

  • Suzuki H, Matsuda S, Terauchi Y, Fujiwara M, Ohteki T, Asano T, Behrens TW, Kouro T, Takatsu K, Kadowaki T, Koyasu S (2003) PI3K and Btk differentially regulate B cell antigen receptor-mediated signal transduction. Nat Immunol 4:280–286

    PubMed  Google Scholar 

  • Swat W, Montgrain V, Doggett TA, Douangpanya J, Puri K, Vermi W, Diacovo TG (2006) Essential role of PI3Kdelta and PI3Kgamma in thymocyte survival. Blood 107:2415–2422

    PubMed  CAS  Google Scholar 

  • Tarasenko T, Dean JA, Bolland S (2007a) FcgammaRIIB as a modulator of autoimmune disease susceptibility. Autoimmunity 40:409–417

    PubMed  CAS  Google Scholar 

  • Tarasenko T, Kole HK, Chi AW, Mentink-Kane MM, Wynn TA, Bolland S (2007b) T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses. Proc Natl Acad Sci USA 104:11382–11387

    PubMed  CAS  Google Scholar 

  • Tassi I, Cella M, Gilfillan S, Turnbull I, Diacovo TG, Penninger JM, Colonna M (2007) p110gamma and p110delta phosphoinositide 3-kinase signaling pathways synergize to control development and functions of murine NK cells. Immunity 27:214–227

    PubMed  CAS  Google Scholar 

  • Thomas MS, Mitchell JS, DeNucci CC, Martin AL, Shimizu Y (2008) The p110gamma isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites. J Leukoc Biol 84:814–823

    PubMed  CAS  Google Scholar 

  • Thome M (2004) CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nat Rev Immunol 4:348–359

    PubMed  CAS  Google Scholar 

  • Tsatsanis C, Vaporidi K, Zacharioudaki V, Androulidaki A, Sykulev Y, Margioris AN, Tsichlis PN (2008) Tpl2 and ERK transduce antiproliferative T cell receptor signals and inhibit transformation of chronically stimulated T cells. Proc Natl Acad Sci USA 105:2987–2992

    PubMed  CAS  Google Scholar 

  • Tze LE, Schram BR, Lam KP, Hogquist KA, Hippen KL, Liu J, Shinton SA, Otipoby KL, Rodine PR, Vegoe AL, Kraus M, Hardy RR, Schlissel MS, Rajewsky K, Behrens TW (2005) Basal immunoglobulin signaling actively maintains developmental stage in immature B cells. PLoS Biol 3:e82

    PubMed  Google Scholar 

  • Verkoczy L, Duong B, Skog P, Ait-Azzouzene D, Puri K, Vela JL, Nemazee D (2007) Basal B cell receptor-directed phosphatidylinositol 3-kinase signaling turns off RAGs and promotes B cell-positive selection. J Immunol 178:6332–6341

    PubMed  CAS  Google Scholar 

  • Vigorito E, Bardi G, Glassford J, Lam EW, Clayton E, Turner M (2004) Vav-dependent and vav-independent phosphatidylinositol 3-kinase activation in murine B cells determined by the nature of the stimulus. J Immunol 173:3209–3214

    PubMed  CAS  Google Scholar 

  • Wagle NM, Faassen AE, Kim JH, Pierce SK (1999) Regulation of B cell receptor-mediated MHC class II antigen processing by FcgammaRIIB1. J Immunol 162:2732–2740

    PubMed  CAS  Google Scholar 

  • Walmsley MJ, Ooi SK, Reynolds LF, Smith SH, Ruf S, Mathiot A, Vanes L, Williams DA, Cancro MP, Tybulewicz VL (2003) Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling. Science 302:459–462

    PubMed  CAS  Google Scholar 

  • Walsh PT, Buckler JL, Zhang J, Gelman AE, Dalton NM, Taylor DK, Bensinger SJ, Hancock WW, Turka LA (2006) PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J Clin Invest 116:2521–2531

    PubMed  CAS  Google Scholar 

  • Waugh C, Sinclair L, Finlay D, Bayascas JR, Cantrell D (2009) Phosphoinositide (3,4,5)-triphosphate binding to phosphoinositide-dependent kinase 1 regulates a protein kinase B/Akt signaling threshold that dictates T-cell migration, not proliferation. Mol Cell Biol 29:5952–5962

    PubMed  CAS  Google Scholar 

  • Webb LM, Vigorito E, Wymann MP, Hirsch E, Turner M (2005) Cutting edge: T cell development requires the combined activities of the p110gamma and p110delta catalytic isoforms of phosphatidylinositol 3-kinase. J Immunol 175:2783–2787

    PubMed  CAS  Google Scholar 

  • Weber M, Treanor B, Depoil D, Shinohara H, Harwood NE, Hikida M, Kurosaki T, Batista FD (2008) Phospholipase C-gamma2 and vav cooperate within signaling microclusters to propagate B cell spreading in response to membrane-bound antigen. J Exp Med 205:853–868

    PubMed  CAS  Google Scholar 

  • Yokosuka T, Kobayashi W, Sakata-Sogawa K, Takamatsu M, Hashimoto-Tane A, Dustin ML, Tokunaga M, Saito T (2008) Spatiotemporal regulation of T cell costimulation by TCR-CD28 microclusters and protein kinase C theta translocation. Immunity 29:589–601

    PubMed  CAS  Google Scholar 

  • Zebedin E, Simma O, Schuster C, Putz EM, Fajmann S, Warsch W, Eckelhart E, Stoiber D, Weisz E, Schmid JA, Pickl WF, Baumgartner C, Valent P, Piekorz RP, Freissmuth M, Sexl V (2008) Leukemic challenge unmasks a requirement for PI3Kdelta in NK cell-mediated tumor surveillance. Blood 112:4655–4664

    PubMed  CAS  Google Scholar 

  • Zhang TT, Okkenhaug K, Nashed BF, Puri KD, Knight ZA, Shokat KM, Vanhaesebroeck B, Marshall AJ (2008) Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production. J Allergy Clin Immunol 122(811–819):e812

    Google Scholar 

  • Zheng Y, Rudensky AY (2007) Foxp3 in control of the regulatory T cell lineage. Nat Immunol 8:457–462

    PubMed  CAS  Google Scholar 

  • Zompi S, Hamerman JA, Ogasawara K, Schweighoffer E, Tybulewicz VL, Di Santo JP, Lanier LL, Colucci F (2003) NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases. Nat Immunol 4:565–572

    PubMed  CAS  Google Scholar 

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Acknowledgments

Work cited from our laboratories has been funded by grants from the BBSRC (to KO) and from the National Institutes of health and the American Cancer Society (to DAF). We are grateful to Dalya Soond and Dan Patton for constructive comments on the manuscript.

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Authors and Affiliations

  1. Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK

    Klaus Okkenhaug

  2. Department of Molecular Biology and Biochemistry, Institute for Immunology, University of California-Irvine, Irvine, CA, 92697-3900, USA

    David A. Fruman

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  1. Klaus Okkenhaug
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Correspondence to Klaus Okkenhaug .

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  1. Intellikine, North Torreye Pines Road 10931, La Jolla, 92037, California, USA

    Christian Rommel

  2. , Institute of Cancer and the London Schoo, Queen Mary, University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom

    Bart Vanhaesebroeck

  3. , Dept. Molecular & Exp. Medicine, Scripps Research Institute, N. Torrey Pines Road 10550, La Jolla, 92037, California, USA

    Peter K. Vogt

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Okkenhaug, K., Fruman, D.A. (2010). PI3Ks in Lymphocyte Signaling and Development. In: Rommel, C., Vanhaesebroeck, B., Vogt, P. (eds) Phosphoinositide 3-kinase in Health and Disease. Current Topics in Microbiology and Immunology, vol 346. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_45

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