Seminars in Immunopathology

, Volume 32, Issue 2, pp 107–116 | Cite as

ZAP70: a master regulator of adaptive immunity

  • Alain Fischer
  • Capucine Picard
  • Karine Chemin
  • Stéphanie Dogniaux
  • Françoise le Deist
  • Claire Hivroz
Review

Abstract

The protein tyrosine kinase ZAP70 became the subject of intense scrutiny in the early nineties, when ZAP70 mutations were characterized in several young patients presenting with severe T cell immunodeficiencies. The association of a lack of expression of ZAP70 with an immunodeficiency consisting in a markedly reduced T lymphocyte-mediated immunity highlighted the crucial role of this tyrosine kinase in T cell development and function. This discovery was soon accompanied by the characterization of the substrates of ZAP70 and the signalling cascades that depend on ZAP70 activity. These studies demonstrated that ZAP70 was indeed at the crossroad of several signalling pathways that control T lymphocyte development and function. Recently, a revival of interest for this protein came again from studies associating abnormal ZAP70 expression with pathological conditions. Some chronic lymphocytic leukemia B cells were shown to express ZAP70, and this expression was correlated with bad prognosis. Mouse models also revealed that partial defects in ZAP70 activity can be associated with autoimmunity. These last results suggested that ZAP70 is involved in the fine balance between immunity and tolerance. In this review, we will discuss the role of ZAP70 in T cell activation and focus on what we learnt from pathological conditions associated with defective expression or activity of the ZAP70 kinase.

Keywords

Immunodeficiency Autoimmunity Tyrosine kinase Immunoreceptor 

References

  1. 1.
    Aguado E, Richelme S, Nunez-Cruz S, Miazek A, Mura AM, Richelme M, Guo XJ, Sainty D, He HT, Malissen B, Malissen M (2002) Induction of T helper type 2 immunity by a point mutation in the LAT adaptor. Science 296:2036–2040CrossRefPubMedGoogle Scholar
  2. 2.
    Alcover A, Alarcon B (2000) Internalization and intracellular fate of TCR-CD3 complexes. Crit Rev Immunol 20:325–346PubMedGoogle Scholar
  3. 3.
    Arpaia E, Shahar M, Dadi H, Cohen A, Roifman CM (1994) Defective T cell receptor signaling and CD8+ thymic selection in humans lacking zap-70 kinase. Cell 76:947–958CrossRefPubMedGoogle Scholar
  4. 4.
    Au-Yeung BB, Deindl S, Hsu LY, Palacios EH, Levin SE, Kuriyan J, Weiss A (2009) The structure, regulation, and function of ZAP-70. Immunol Rev 228:41–57CrossRefPubMedGoogle Scholar
  5. 5.
    Barata LT, Henriques R, Hivroz C, Jouanguy E, Paiva A, Freitas AM, Coimbra HB, Fischer A, da Mota HC (2001) Primary immunodeficiency secondary to ZAP-70 deficiency. Acta Med Port 14:413–417PubMedGoogle Scholar
  6. 6.
    Barda-Saad M, Braiman A, Titerence R, Bunnell SC, Barr VA, Samelson LE (2005) Dynamic molecular interactions linking the T cell antigen receptor to the actin cytoskeleton. Nat Immunol 6:80–89CrossRefPubMedGoogle Scholar
  7. 7.
    Blanchard N, Di Bartolo V, Hivroz C (2002) In the immune synapse, ZAP-70 controls T cell polarization and recruitment of signaling proteins but not formation of the synaptic pattern. Immunity 17:389–399CrossRefPubMedGoogle Scholar
  8. 8.
    Bonello G, Blanchard N, Montoya MC, Aguado E, Langlet C, He HT, Nunez-Cruz S, Malissen M, Sanchez-Madrid F, Olive D, Hivroz C, Collette Y (2004) Dynamic recruitment of the adaptor protein LAT: LAT exists in two distinct intracellular pools and controls its own recruitment. J Cell Sci 117:1009–1016CrossRefPubMedGoogle Scholar
  9. 9.
    Brdicka T, Kadlecek TA, Roose JP, Pastuszak AW, Weiss A (2005) Intramolecular regulatory switch in ZAP-70: analogy with receptor tyrosine kinases. Mol Cell Biol 25:4924–4933CrossRefPubMedGoogle Scholar
  10. 10.
    Bu JY, Shaw AS, Chan AC (1995) Analysis of the interaction of ZAP-70 and syk protein-tyrosine kinases with the T-cell antigen receptor by plasmon resonance. Proc Natl Acad Sci USA 92:5106–5110CrossRefPubMedGoogle Scholar
  11. 11.
    Bubeck Wardenburg J, Pappu R, Bu JY, Mayer B, Chernoff J, Straus D, Chan AC (1998) Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76. Immunity 9:607–616CrossRefPubMedGoogle Scholar
  12. 12.
    Chan AC, Dalton M, Johnson R, Kong GH, Wang T, Thoma R, Kurosaki T (1995) Activation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function. EMBO J 14:2499–2508PubMedGoogle Scholar
  13. 13.
    Chan AC, Iwashima M, Turck CW, Weiss A (1992) ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell 71:649–662CrossRefPubMedGoogle Scholar
  14. 14.
    Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL, Iwashima M, Parslow TG, Weiss A (1994) ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science 264:1599–1601CrossRefPubMedGoogle Scholar
  15. 15.
    Chen L, Apgar J, Huynh L, Dicker F, Giago-McGahan T, Rassenti L, Weiss A, Kipps TJ (2005) ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood 105:2036–2041CrossRefPubMedGoogle Scholar
  16. 16.
    Chen L, Huynh L, Apgar J, Tang L, Rassenti L, Weiss A, Kipps TJ (2008) ZAP-70 enhances IgM signaling independent of its kinase activity in chronic lymphocytic leukemia. Blood 111:2685–2692CrossRefPubMedGoogle Scholar
  17. 17.
    Chen L, Widhopf G, Huynh L, Rassenti L, Rai KR, Weiss A, Kipps TJ (2002) Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood 100:4609–4614CrossRefPubMedGoogle Scholar
  18. 18.
    Cheng AM, Rowley B, Pao W, Hayday A, Bolen JB, Pawson T (1995) Syk tyrosine kinase required for mouse viability and B-cell development. Nature 378:303–306CrossRefPubMedGoogle Scholar
  19. 19.
    Chu DH, van Oers NS, Malissen M, Harris J, Elder M, Weiss A (1999) Pre-T cell receptor signals are responsible for the down-regulation of Syk protein tyrosine kinase expression. J Immunol 163:2610–2620PubMedGoogle Scholar
  20. 20.
    Davanture S, Leignadier J, Milani P, Soubeyran P, Malissen B, Malissen M, Schmitt-Verhulst AM, Boyer C (2005) Selective defect in antigen-induced TCR internalization at the immune synapse of CD8 T cells bearing the ZAP-70(Y292F) mutation. J Immunol 175:3140–3149PubMedGoogle Scholar
  21. 21.
    Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J (2007) Structural basis for the inhibition of tyrosine kinase activity of ZAP-70. Cell 129:735–746CrossRefPubMedGoogle Scholar
  22. 22.
    Di Bartolo V, Mege D, Germain V, Pelosi M, Dufour E, Michel F, Magistrelli G, Isacchi A, Acuto O (1999) Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling. J Biol Chem 274:6285–6294CrossRefPubMedGoogle Scholar
  23. 23.
    Dong S, Corre B, Foulon E, Dufour E, Veillette A, Acuto O, Michel F (2006) T cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2. J Exp Med 203:2509–2518CrossRefPubMedGoogle Scholar
  24. 24.
    Dumont C, Blanchard N, Di Bartolo V, Lezot N, Dufour E, Jauliac S, Hivroz C (2002) TCR/CD3 down-modulation and zeta degradation are regulated by ZAP-70. J Immunol 169:1705–1712PubMedGoogle Scholar
  25. 25.
    Duplay P, Thome M, Herve F, Acuto O (1994) p56lck interacts via its src homology 2 domain with the ZAP-70 kinase. J Exp Med 179:1163–1172CrossRefPubMedGoogle Scholar
  26. 26.
    Elder ME, Hope TJ, Parslow TG, Umetsu DT, Wara DW, Cowan MJ (1995) Severe combined immunodeficiency with absence of peripheral blood CD8+ T cells due to ZAP-70 deficiency. Cell Immunol 165:110–117CrossRefPubMedGoogle Scholar
  27. 27.
    Elder ME, Lin D, Clever J, Chan AC, Hope TJ, Weiss A, Parslow TG (1994) Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264:1596–1599CrossRefPubMedGoogle Scholar
  28. 28.
    Elder ME, Skoda-Smith S, Kadlecek TA, Wang F, Wu J, Weiss A (2001) Distinct T cell developmental consequences in humans and mice expressing identical mutations in the DLAARN motif of ZAP-70. J Immunol 166:656–661PubMedGoogle Scholar
  29. 29.
    Epler JA, Liu R, Chung H, Ottoson NC, Shimizu Y (2000) Regulation of beta 1 integrin-mediated adhesion by T cell receptor signaling involves ZAP-70 but differs from signaling events that regulate transcriptional activity. J Immunol 165:4941–4949PubMedGoogle Scholar
  30. 30.
    Fagioli F, Biasin E, Berger M, Nesi F, Saroglia EH, Miniero R, Martino S, Tovo PA (2003) Successful unrelated cord blood transplantation in two children with severe combined immunodeficiency syndrome. Bone Marrow Transplant 31:133–136CrossRefPubMedGoogle Scholar
  31. 31.
    Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441:179–185CrossRefPubMedGoogle Scholar
  32. 32.
    Finco TS, Kadlecek T, Zhang W, Samelson LE, Weiss A (1998) LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway. Immunity 9:617–626CrossRefPubMedGoogle Scholar
  33. 33.
    Gelkop S, Isakov N (1999) T cell activation stimulates the association of enzymatically active tyrosine-phosphorylated ZAP-70 with the Crk adapter proteins. J Biol Chem 274:21519–21527CrossRefPubMedGoogle Scholar
  34. 34.
    Genton C, Wang Y, Izui S, Malissen B, Delsol G, Fournie GJ, Malissen M, Acha-Orbea H (2006) The Th2 lymphoproliferation developing in LatY136F mutant mice triggers polyclonal B cell activation and systemic autoimmunity. J Immunol 177:2285–2293PubMedGoogle Scholar
  35. 35.
    Goda S, Quale AC, Woods ML, Felthauser A, Shimizu Y (2004) Control of TCR-mediated activation of beta 1 integrins by the ZAP-70 tyrosine kinase interdomain B region and the linker for activation of T cells adapter protein. J Immunol 172:5379–5387PubMedGoogle Scholar
  36. 36.
    Hatada MH, Lu X, Laird ER, Green J, Morgenstern JP, Lou M, Marr CS, Phillips TB, Ram MK, Theriault K et al (1995) Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor. Nature 377:32–38CrossRefPubMedGoogle Scholar
  37. 37.
    Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, Iwakura Y, Sakaguchi N, Sakaguchi S (2007) T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J Exp Med 204:41–47CrossRefPubMedGoogle Scholar
  38. 38.
    Houtman JC, Houghtling RA, Barda-Saad M, Toda Y, Samelson LE (2005) Early phosphorylation kinetics of proteins involved in proximal TCR-mediated signaling pathways. J Immunol 175:2449–2458PubMedGoogle Scholar
  39. 39.
    Kadlecek TA, van Oers NS, Lefrancois L, Olson S, Finlay D, Chu DH, Connolly K, Killeen N, Weiss A (1998) Differential requirements for ZAP-70 in TCR signaling and T cell development. J Immunol 161:4688–4694PubMedGoogle Scholar
  40. 40.
    Katamura K, Tai G, Tachibana T, Yamabe H, Ohmori K, Mayumi M, Matsuda S, Koyasu S, Furusho K (1999) Existence of activated and memory CD4+ T cells in peripheral blood and their skin infiltration in CD8 deficiency. Clin Exp Immunol 115:124–130CrossRefPubMedGoogle Scholar
  41. 41.
    Krangel MS (1987) Endocytosis and recycling of the T3-T cell receptor complex. The role of T3 phosphorylation. J Exp Med 165:1141–1159CrossRefPubMedGoogle Scholar
  42. 42.
    Le Deist F, Hivroz C, Partiseti M, Thomas C, Buc HA, Oleastro M, Belohradsky B, Choquet D, Fischer A (1995) A primary T-cell immunodeficiency associated with defective transmembrane calcium influx. Blood 85:1053–1062PubMedGoogle Scholar
  43. 43.
    Liu H, Rhodes M, Wiest DL, Vignali DAA (2000) On the dynamics of TCR:CD3 complex cell surface expression and downmodulation. Immunity 13:665–675CrossRefPubMedGoogle Scholar
  44. 44.
    Lupher ML Jr, Songyang Z, Shoelson SE, Cantley LC, Band H (1997) The Cbl phosphotyrosine-binding domain selects a D(N/D)XpY motif and binds to the Tyr292 negative regulatory phosphorylation site of ZAP-70. J Biol Chem 272:33140–33144CrossRefPubMedGoogle Scholar
  45. 45.
    Magnan A, Di Bartolo V, Mura AM, Boyer C, Richelme M, Lin YL, Roure A, Gillet A, Arrieumerlou C, Acuto O, Malissen B, Malissen M (2001) T cell development and T cell responses in mice with mutations affecting tyrosines 292 or 315 of the ZAP-70 protein tyrosine kinase. J Exp Med 194:491–505CrossRefPubMedGoogle Scholar
  46. 46.
    Matsuda S, Suzuki-Fujimoto T, Minowa A, Ueno H, Katamura K, Koyasu S (1999) Temperature-sensitive ZAP70 mutants degrading through a proteasome-independent pathway. Restoration of a kinase domain mutant by Cdc37. J Biol Chem 274:34515–34518CrossRefPubMedGoogle Scholar
  47. 47.
    Mazer B, Harbeck RJ, Franklin R, Schwinzer R, Kubo R, Hayward A, Gelfand EW (1997) Phenotypic features of selective T cell deficiency characterized by absence of CD8+ T lymphocytes and undetectable mRNA for ZAP-70 kinase. Clin Immunol Immunopathol 84:129–138CrossRefPubMedGoogle Scholar
  48. 48.
    Meinl E, Derfuss T, Pirzer R, Blank N, Lengenfelder D, Blancher A, Le Deist F, Fleckenstein B, Hivroz C (2001) Herpesvirus saimiri replaces ZAP-70 for CD3- and CD2-mediated T cell activation. J Biol Chem 276:36902–36908CrossRefPubMedGoogle Scholar
  49. 49.
    Meinl E, Lengenfelder D, Blank N, Pirzer R, Barata L, Hivroz C (2000) Differential requirement of ZAP-70 for CD2-mediated activation pathways of mature human T cells. J Immunol 165:3578–3583PubMedGoogle Scholar
  50. 50.
    Minami Y, Samelson LE, Klausner RD (1987) Internalization and cycling of the T cell antigen receptor. Role of protein kinase C. J Biol Chem 262:13342–13347PubMedGoogle Scholar
  51. 51.
    Mingueneau M, Roncagalli R, Gregoire C, Kissenpfennig A, Miazek A, Archambaud C, Wang Y, Perrin P, Bertosio E, Sansoni A, Richelme S, Locksley RM, Aguado E, Malissen M, Malissen B (2009) Loss of the LAT adaptor converts antigen-responsive T cells into pathogenic effectors that function independently of the T cell receptor. Immunity 31:197–208CrossRefPubMedGoogle Scholar
  52. 52.
    Negishi I, Motoyama N, Nakayama K, Senju S, Hatakeyama S, Zhang Q, Chan AC, Loh DY (1995) Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376:435–438CrossRefPubMedGoogle Scholar
  53. 53.
    Noraz N, Schwarz K, Steinberg M, Dardalhon V, Rebouissou C, Hipskind R, Friedrich W, Yssel H, Bacon K, Taylor N (2000) Alternative antigen receptor (TCR) signaling in T cells derived from ZAP-70-deficient patients expressing high levels of Syk. J Biol Chem 275:15832–15838CrossRefPubMedGoogle Scholar
  54. 54.
    Orchard JA, Ibbotson RE, Davis Z, Wiestner A, Rosenwald A, Thomas PW, Hamblin TJ, Staudt LM, Oscier DG (2004) ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363:105–111CrossRefPubMedGoogle Scholar
  55. 55.
    Pelosi M, Di Bartolo V, Mounier V, Mege D, Pascussi JM, Dufour E, Blondel A, Acuto O (1999) Tyrosine 319 in the interdomain B of ZAP-70 is a binding site for the Src homology 2 domain of Lck. J Biol Chem 274:14229–14237CrossRefPubMedGoogle Scholar
  56. 56.
    Picard C, Dogniaux S, Chemin K, Maciorowski Z, Lim A, Mazerolles F, Rieux-Laucat F, Stolzenberg MC, Debre M, Magny JP, Le Deist F, Fischer A, Hivroz C (2009) Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity. Eur J Immunol 39:1966–1976CrossRefPubMedGoogle Scholar
  57. 57.
    Picard C, McCarl CA, Papolos A, Khalil S, Luthy K, Hivroz C, LeDeist F, Rieux-Laucat F, Rechavi G, Rao A, Fischer A, Feske S (2009) STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N Engl J Med 360:1971–1980CrossRefPubMedGoogle Scholar
  58. 58.
    Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG, Neuberg DS, Flinn IW, Rai KR, Byrd JC, Kay NE, Greaves A, Weiss A, Kipps TJ (2004) ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 351:893–901CrossRefPubMedGoogle Scholar
  59. 59.
    Reinherz EL, Acuto O, Fabbi M, Bensussan A, Milanese C, Royer HD, Meuer SC, Schlossman SF (1984) Clonotypic surface structure on human T lymphocytes: functional and biochemical analysis of the antigen receptor complex. Immunol Rev 81:95–129CrossRefPubMedGoogle Scholar
  60. 60.
    Roifman CM (2005) Studies of patients' thymi aid in the discovery and characterization of immunodeficiency in humans. Immunol Rev 203:143–155CrossRefPubMedGoogle Scholar
  61. 61.
    Roifman CM, Hummel D, Martinez-Valdez H, Thorner P, Doherty PJ, Pan S, Cohen F, Cohen A (1989) Depletion of CD8+ cells in human thymic medulla results in selective immune deficiency. J Exp Med 170:2177–2182CrossRefPubMedGoogle Scholar
  62. 62.
    Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X, Yang L, Pickeral OK, Rassenti LZ, Powell J, Botstein D, Byrd JC, Grever MR, Cheson BD, Chiorazzi N, Wilson WH, Kipps TJ, Brown PO, Staudt LM (2001) Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 194:1639–1647CrossRefPubMedGoogle Scholar
  63. 63.
    Sakaguchi S, Sakaguchi N, Yoshitomi H, Hata H, Takahashi T, Nomura T (2006) Spontaneous development of autoimmune arthritis due to genetic anomaly of T cell signal transduction: part 1. Semin Immunol 18:199–206CrossRefPubMedGoogle Scholar
  64. 64.
    Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T, Yamazaki S, Sakihama T, Matsutani T, Negishi I, Nakatsuru S, Sakaguchi S (2003) Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426:454–460CrossRefPubMedGoogle Scholar
  65. 65.
    Sasahara Y, Rachid R, Byrne MJ, de la Fuente MA, Abraham RT, Ramesh N, Geha RS (2002) Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation. Mol Cell 10:1269–1281CrossRefPubMedGoogle Scholar
  66. 66.
    Schweighoffer E, Vanes L, Mathiot A, Nakamura T, Tybulewicz VL (2003) Unexpected requirement for ZAP-70 in pre-B cell development and allelic exclusion. Immunity 18:523–533CrossRefPubMedGoogle Scholar
  67. 67.
    Siggs OM, Miosge LA, Yates AL, Kucharska EM, Sheahan D, Brdicka T, Weiss A, Liston A, Goodnow CC (2007) Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions. Immunity 27:912–926CrossRefPubMedGoogle Scholar
  68. 68.
    Soede RD, Wijnands YM, Van Kouteren-Cobzaru I, Roos E (1998) ZAP-70 tyrosine kinase is required for LFA-1-dependent T cell migration. J Cell Biol 142:1371–1379CrossRefPubMedGoogle Scholar
  69. 69.
    Sommers CL, Dejarnette JB, Huang K, Lee J, El-Khoury D, Shores EW, Love PE (2000) Function of CD3 epsilon-mediated signals in T cell development. J Exp Med 192:913–919CrossRefPubMedGoogle Scholar
  70. 70.
    Sommers CL, Lee J, Steiner KL, Gurson JM, Depersis CL, El-Khoury D, Fuller CL, Shores EW, Love PE, Samelson LE (2005) Mutation of the phospholipase C-gamma1-binding site of LAT affects both positive and negative thymocyte selection. J Exp Med 201:1125–1134CrossRefPubMedGoogle Scholar
  71. 71.
    Sommers CL, Park CS, Lee J, Feng C, Fuller CL, Grinberg A, Hildebrand JA, Lacana E, Menon RK, Shores EW, Samelson LE, Love PE (2002) A LAT mutation that inhibits T cell development yet induces lymphoproliferation. Science 296:2040–2043CrossRefPubMedGoogle Scholar
  72. 72.
    Steinberg M, Swainson L, Schwarz K, Boyer M, Friedrich W, Yssel H, Taylor N, Noraz N (2000) Retrovirus-mediated transduction of primary ZAP-70-deficient human T cells results in the selective growth advantage of gene-corrected cells: implications for gene therapy. Gene Ther 7:1392–1400CrossRefPubMedGoogle Scholar
  73. 73.
    Thome M, Duplay P, Guttinger M, Acuto O (1995) Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex. J Exp Med 181:1997–2006CrossRefPubMedGoogle Scholar
  74. 74.
    Ticchioni M, Charvet C, Noraz N, Lamy L, Steinberg M, Bernard A, Deckert M (2002) Signaling through ZAP-70 is required for CXCL12-mediated T-cell transendothelial migration. Blood 99:3111–3118CrossRefPubMedGoogle Scholar
  75. 75.
    Tolusso B, De Santis M, Bosello S, Gremese E, Gobessi S, Cuoghi I, Totaro MC, Bigotti G, Rumi C, Efremov DG, Ferraccioli G (2009) Synovial B cells of rheumatoid arthritis express ZAP-70 which increases the survival and correlates with the inflammatory and autoimmune phenotype. Clin Immunol 131:98–108CrossRefPubMedGoogle Scholar
  76. 76.
    Toyabe S, Watanabe A, Harada W, Karasawa T, Uchiyama M (2001) Specific immunoglobulin E responses in ZAP-70-deficient patients are mediated by Syk-dependent T-cell receptor signalling. Immunology 103:164–171CrossRefPubMedGoogle Scholar
  77. 77.
    Turner M, Mee PJ, Costello PS, Williams O, Price AA, Duddy LP, Furlong MT, Geahlen RL, Tybulewicz VL (1995) Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature 378:298–302CrossRefPubMedGoogle Scholar
  78. 78.
    Turul T, Tezcan I, Artac H, de Bruin-Versteeg S, Barendregt BH, Reisli I, Sanal O, van Dongen JJ, van der Burg M (2009) Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency. Eur J Pediatr 168:87–93CrossRefPubMedGoogle Scholar
  79. 79.
    Valitutti S, Muller S, Cella M, Padovan E, Lanzavecchia A (1995) Serial triggering of many T-cell receptors by a few peptide-MHC complexes [see comments]. Nature 375:148–151CrossRefPubMedGoogle Scholar
  80. 80.
    Valitutti S, Muller S, Dessing M, Lanzavecchia A (1996) Signal extinction and T cell repolarization in T helper cell-antigen-presenting cell conjugates. Eur J Immunol 26:2012–2016CrossRefPubMedGoogle Scholar
  81. 81.
    Wang HY, Altman Y, Fang D, Elly C, Dai Y, Shao Y, Liu YC (2001) Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70. J Biol Chem 276:26004–26011CrossRefPubMedGoogle Scholar
  82. 82.
    Wang Y, Kissenpfennig A, Mingueneau M, Richelme S, Perrin P, Chevrier S, Genton C, Lucas B, DiSanto JP, Acha-Orbea H, Malissen B, Malissen M (2008) Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells. J Immunol 180:1565–1575PubMedGoogle Scholar
  83. 83.
    Wange RL, Guitian R, Isakov N, Watts JD, Aebersold R, Samelson LE (1995) Activating and inhibitory mutations in adjacent tyrosines in the kinase domain of ZAP-70. J Biol Chem 270:18730–18733CrossRefPubMedGoogle Scholar
  84. 84.
    Weil R, Cloutier JF, Fournel M, Veillette A (1995) Regulation of Zap-70 by Src family tyrosine protein kinases in an antigen-specific T-cell line. J Biol Chem 270:2791–2799CrossRefPubMedGoogle Scholar
  85. 85.
    Wiest DL, Ashe JM, Howcroft TK, Lee HM, Kemper DM, Negishi I, Singer DS, Singer A, Abe R (1997) A spontaneously arising mutation in the DLAARN motif of murine ZAP-70 abrogates kinase activity and arrests thymocyte development. Immunity 6:663–671CrossRefPubMedGoogle Scholar
  86. 86.
    Wiest DL, Yuan L, Jefferson J, Benveniste P, Tsokos M, Klausner RD, Glimcher LH, Samelson LE, Singer A (1993) Regulation of T cell receptor expression in immature CD4 + CD8+ thymocytes by p56lck tyrosine kinase: basis for differential signaling by CD4 and CD8 in immature thymocytes expressing both coreceptor molecules. J Exp Med 178:1701–1712CrossRefPubMedGoogle Scholar
  87. 87.
    Williams BL, Irvin BJ, Sutor SL, Chini CC, Yacyshyn E, Bubeck Wardenburg J, Dalton M, Chan AC, Abraham RT (1999) Phosphorylation of Tyr319 in ZAP-70 is required for T-cell antigen receptor-dependent phospholipase C-gamma1 and Ras activation. EMBO J 18:1832–1844CrossRefPubMedGoogle Scholar
  88. 88.
    Williams BL, Schreiber KL, Zhang W, Wange RL, Samelson LE, Leibson PJ, Abraham RT (1998) Genetic evidence for differential coupling of Syk family kinases to the T-cell receptor: reconstitution studies in a ZAP-70-deficient Jurkat T-cell line. Mol Cell Biol 18:1388–1399PubMedGoogle Scholar
  89. 89.
    Yamasaki S, Nishida K, Sakuma M, Berry D, McGlade CJ, Hirano T, Saito T (2003) Gads/Grb2-mediated association with LAT is critical for the inhibitory function of Gab2 in T cells. Mol Cell Biol 23:2515–2529CrossRefPubMedGoogle Scholar
  90. 90.
    Yasuda T, Bundo K, Hino A, Honda K, Inoue A, Shirakata M, Osawa M, Tamura T, Nariuchi H, Oda H, Yamamoto T, Yamanashi Y (2007) Dok-1 and Dok-2 are negative regulators of T cell receptor signaling. Int Immunol 19:487–495CrossRefPubMedGoogle Scholar
  91. 91.
    Yoshitomi H, Sakaguchi N, Kobayashi K, Brown GD, Tagami T, Sakihama T, Hirota K, Tanaka S, Nomura T, Miki I, Gordon S, Akira S, Nakamura T, Sakaguchi S (2005) A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J Exp Med 201:949–960CrossRefPubMedGoogle Scholar
  92. 92.
    Zanders ED, Lamb JR, Feldmann M, Green N, Beverley PC (1983) Tolerance of T-cell clones is associated with membrane antigen changes. Nature 303:625–627CrossRefPubMedGoogle Scholar
  93. 93.
    Zhang W, Irvin BJ, Trible RP, Abraham RT, Samelson LE (1999) Functional analysis of LAT in TCR-mediated signaling pathways using a LAT-deficient Jurkat cell line. Int Immunol 11:943–950CrossRefPubMedGoogle Scholar
  94. 94.
    Zhao Q, Weiss A (1996) Enhancement of lymphocyte responsiveness by a gain-of-function mutation of ZAP-70. Mol Cell Biol 16:6765–6774PubMedGoogle Scholar
  95. 95.
    Zhao Q, Williams BL, Abraham RT, Weiss A (1999) Interdomain B in ZAP-70 regulates but is not required for ZAP-70 signaling function in lymphocytes. Mol Cell Biol 19:948–956PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Alain Fischer
    • 1
    • 2
    • 3
  • Capucine Picard
    • 3
    • 4
    • 5
  • Karine Chemin
    • 6
    • 7
  • Stéphanie Dogniaux
    • 6
    • 7
  • Françoise le Deist
    • 8
  • Claire Hivroz
    • 6
    • 7
  1. 1.INSERM, U768, Hôpital Necker-Enfants MaladesParisFrance
  2. 2.Unité d’Immuno-Hématologie Pédiatrique, Assistance Publique-Hôpitaux de ParisHôpital Necker-Enfants MaladesParisFrance
  3. 3.Faculté NeckerUniversité Paris DescartesParisFrance
  4. 4.Centre d’Étude des Déficits Immunitaires, Assistance Publique-Hôpitaux de ParisHôpital Necker-Enfants MaladesParisFrance
  5. 5.Génétique Humaine des Maladies Infectieuses, Faculté NeckerINSERM, Unité 550ParisFrance
  6. 6.Centre de RechercheInstitut CurieParisFrance
  7. 7.Immunité et CancerINSERM, Unité 932ParisFrance
  8. 8.Department of Microbiology and Immunology, and Centre of Research, CHU Sainte-JustineUniversité de MontréalMontrealCanada

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