1932

Abstract

T cells possess an array of functional capabilities important for host defense against pathogens and tumors. T cell effector functions require the T cell antigen receptor (TCR). The TCR has no intrinsic enzymatic activity, and thus signal transduction from the receptor relies on additional signaling molecules. One such molecule is the cytoplasmic tyrosine kinase ZAP-70, which associates with the TCR complex and is required for initiating the canonical biochemical signal pathways downstream of the TCR. In this article, we describe recent structure-based insights into the regulation and substrate specificity of ZAP-70, and then we review novel methods for determining the role of ZAP-70 catalytic activity–dependent and –independent signals in developing and mature T cells. Lastly, we discuss the disease states in mouse models and humans, which range from immunodeficiency to autoimmunity, that are caused by mutations in ZAP-70.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-042617-053335
2018-04-26
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/immunol/36/1/annurev-immunol-042617-053335.html?itemId=/content/journals/10.1146/annurev-immunol-042617-053335&mimeType=html&fmt=ahah

Literature Cited

  1. Chakraborty AK, Weiss A. 1.  2014. Insights into the initiation of TCR signaling. Nat. Immunol. 15:798–807 [Google Scholar]
  2. Weiss A. 2.  1993. T cell antigen receptor signal transduction: a tale of tails and cytoplasmic protein-tyrosine kinases. Cell 73:209–12 [Google Scholar]
  3. Iwashima M, Irving BA, van Oers NS, Chan AC, Weiss A. 3.  1994. Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases. Science 263:1136–39 [Google Scholar]
  4. Thill PA, Weiss A, Chakraborty AK. 4.  2016. Phosphorylation of a tyrosine residue on Zap70 by Lck and its subsequent binding via an SH2 domain may be a key gatekeeper of T cell receptor signaling in vivo. Mol. Cell Biol. 36:2396–402 [Google Scholar]
  5. van Oers NS, Killeen N, Weiss A. 5.  1994. ZAP-70 is constitutively associated with tyrosine-phosphorylated TCR zeta in murine thymocytes and lymph node T cells. Immunity 1:675–85 [Google Scholar]
  6. Stefanova I, Dorfman JR, Germain RN. 6.  2002. Self-recognition promotes the foreign antigen sensitivity of naive T lymphocytes. Nature 420:429–34 [Google Scholar]
  7. van Oers NS, Killeen N, Weiss A. 7.  1996. Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes. J. Exp. Med. 183:1053–62 [Google Scholar]
  8. Chan AC, Irving BA, Fraser JD, Weiss A. 8.  1991. The zeta chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein. PNAS 88:9166–70 [Google Scholar]
  9. Chan AC, Iwashima M, Turck CW, Weiss A. 9.  1992. ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR ζ chain. Cell 71:649–62 [Google Scholar]
  10. Moscai A, Ruland J, Tybulewicz VL. 10.  2010. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat. Immunol. 10:387–402 [Google Scholar]
  11. Flajnik MF, Kasahara M. 11.  2010. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat. Rev. Genet. 11:47–59 [Google Scholar]
  12. Wange RL, Malek SN, Desiderio S, Samelson LE. 12.  1993. Tandem SH2 domains of ZAP-70 bind to T cell antigen receptor ζ and CD3ε from activated Jurkat T cells. J. Biol. Chem. 268:19797–801 [Google Scholar]
  13. Isakov N, Wange RL, Burgess WH, Watts JD, Aebersold R, Samelson LE. 13.  1995. ZAP-70 binding specificity to T cell receptor tyrosine-based activation motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based activation motifs with varying affinity. J. Exp. Med. 181:375–80 [Google Scholar]
  14. Ottinger EA, Botfield MC, Shoelson SE. 14.  1998. Tandem SH2 domains confer high specificity in tyrosine kinase signaling. J. Biol. Chem. 273:729–35 [Google Scholar]
  15. Hatada MH, Lu X, Laird ER, Green J, Morgenstern JP. 15.  et al. 1995. Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor. Nature 377:32–38 [Google Scholar]
  16. Folmer RH, Geschwindner S, Xue Y. 16.  2002. Crystal structure and NMR studies of the apo SH2 domains of ZAP-70: two bikes rather than a tandem. Biochemistry 41:14176–84 [Google Scholar]
  17. Marengere LEM, Songyang Z, Gish GD, Schaller MD, Parsons JT. 17.  et al. 1994. SH2 domain specificity and activity modified by a single residue. Nature 369:502–5 [Google Scholar]
  18. Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J. 18.  2007. Structural basis for the inhibition of tyrosine kinase activity of ZAP-70. Cell 129:735–46 [Google Scholar]
  19. Yan Q, Barros T, Visperas PR, Deindl S, Kadlecek TA. 19.  et al. 2013. Structural basis for activation of ZAP-70 by phosphorylation of the SH2-kinase linker. Mol. Cell Biol. 33:2188–201 [Google Scholar]
  20. Sicheri F, Moarefi I, Kuriyan J. 20.  1997. Crystal structure of the Src family tyrosine kinase Hck. Nature 385:602–9 [Google Scholar]
  21. Jin L, Pluskey S, Petrella EC, Cantin SM, Gorga JC. 21.  et al. 2004. The three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine: implications for the design of selective inhibitors. J. Biol. Chem. 279:42818–25 [Google Scholar]
  22. Klammt C, Novotna L, Li DT, Wolf M, Blount A. 22.  et al. 2015. T cell receptor dwell times control the kinase activity of Zap70. Nat. Immunol. 16:961–69 [Google Scholar]
  23. Brdicka T, Kadlecek TA, Roose JP, Pastuszak AW, Weiss A. 23.  2005. Intramolecular regulatory switch in ZAP-70: analogy with receptor tyrosine kinases. Mol. Cell Biol. 25:4924–33 [Google Scholar]
  24. Deindl S, Kadlecek TA, Cao X, Kuriyan J, Weiss A. 24.  2009. Stability of an autoinhibitory interface in the structure of the tyrosine kinase ZAP-70 impacts T cell receptor response. PNAS 106:20699–704 [Google Scholar]
  25. Hsu LY, Cheng DA, Chen Y, Liang HE, Weiss A. 25.  2017. Destabilizing the autoinhibitory conformation of Zap70 induces up-regulation of inhibitory receptors and T cell unresponsiveness. J. Exp. Med. 214:833–49 [Google Scholar]
  26. Chan AY, Punwani D, Kadlecek TA, Cowan MJ, Olson JL. 26.  et al. 2016. A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70. J. Exp. Med. 213:155–65 [Google Scholar]
  27. Zhao Q, Williams BL, Abraham RT, Weiss A. 27.  1999. Interdomain B in ZAP-70 regulates but is not required for ZAP-70 signaling function in lymphocytes. Mol. Cell Biol. 19:948–56 [Google Scholar]
  28. Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE. 28.  1998. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell 92:83–92 [Google Scholar]
  29. Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE. 29.  et al. 1996. Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J. Biol. Chem. 271:19641–44 [Google Scholar]
  30. Koretzky GA, Abtahian F, Silverman MA. 30.  2006. SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nat. Rev. Immunol. 6:67–78 [Google Scholar]
  31. Su X, Ditlev JA, Hui E, Xing W, Banjade S. 31.  et al. 2016. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352:595–99 [Google Scholar]
  32. Balagopalan L, Coussens NP, Sherman E, Samelson LE, Sommers CL. 32.  2010. The LAT story: a tale of cooperativity, coordination, and choreography. Cold Spring Harb. Perspect. Biol. 2:a005512 [Google Scholar]
  33. Salvador JM, Mittelstadt PR, Guszczynski T, Copeland TD, Yamaguchi H. 33.  et al. 2005. Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat. Immunol. 6:390–95 [Google Scholar]
  34. Roncagalli R, Hauri S, Fiore F, Liang Y, Chen Z. 34.  et al. 2014. Quantitative proteomics analysis of signalosome dynamics in primary T cells identifies the surface receptor CD6 as a Lat adaptor-independent TCR signaling hub. Nat. Immunol. 15:384–92 [Google Scholar]
  35. Ferrando IM, Chaerkady R, Zhong J, Molina H, Jacob HK. 35.  et al. 2012. Identification of targets of c-Src tyrosine kinase by chemical complementation and phosphoproteomics. Mol. Cell Proteom. 11:355–69 [Google Scholar]
  36. Shah NH, Wang Q, Yan Q, Karandur D, Kadlecek TA. 36.  et al. 2016. An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor. eLife 5:e20105 [Google Scholar]
  37. Isakov N, Wange RL, Watts JD, Aebersold R, Samelson LE. 37.  1996. Purification and characterization of human ZAP-70 protein-tyrosine kinase from a baculovirus expression system. J. Biol. Chem. 271:15753–61 [Google Scholar]
  38. Deng Y, Alicea-Velazquez NL, Bannwarth L, Lehtonen SI, Boggon TJ. 38.  et al. 2014. Global analysis of human nonreceptor tyrosine kinase specificity using high-density peptide microarrays. J. Proteome Res. 13:4339–46 [Google Scholar]
  39. Xue L, Wang W-H, Iliuk A, Hu L, Galan JA. 39.  et al. 2012. Sensitive kinase assay linked with phosphoproteomics for identifying direct kinase substrates. PNAS 109:5615–20 [Google Scholar]
  40. Schmitz R, Baumann G, Gram H. 40.  1996. Catalytic specificity of phosphotyrosine kinases Blk, Lyn, c-Src and Syk as assessed by phage display. J. Mol. Biol. 260:664–77 [Google Scholar]
  41. Houtman JCD, Yamaguchi H, Barda-Saad M, Braiman A, Bowden B. 41.  et al. 2006. Oligomerization of signaling complexes by the multipoint binding of GRB2 to both LAT and SOS1. Nat. Struct. Mol. Biol. 13:798–805 [Google Scholar]
  42. Houtman JCD, Houghtling RA, Barda-Saad M, Toda Y, Samelson LE. 42.  2005. Early phosphorylation kinetics of proteins involved in proximal TCR-mediated signaling pathways. J. Immunol. 175:2449–58 [Google Scholar]
  43. Au-Yeung BB, Levin SE, Zhang C, Hsu LY, Cheng DA. 43.  et al. 2010. A genetically selective inhibitor demonstrates a function for the kinase Zap70 in regulatory T cells independent of its catalytic activity. Nat. Immunol. 11:1085–92 [Google Scholar]
  44. Roncagalli R, Mingueneau M, Grégoire C, Malissen M, Malissen B. 44.  2010. LAT signaling pathology: an “autoimmune” condition without T cell self-reactivity. Trends Immunol 31:253–59 [Google Scholar]
  45. McKeithan TW. 45.  1995. Kinetic proofreading in T-cell receptor signal transduction. PNAS 92:5042–46 [Google Scholar]
  46. Tsang E, Giannetti AM, Shaw D, Dinh M, Tse JK. 46.  et al. 2008. Molecular mechanism of the Syk activation switch. J. Biol. Chem. 283:32650–59 [Google Scholar]
  47. Mukherjee S, Zhu J, Zikherman J, Parameswaran R, Kadlecek TA. 47.  et al. 2013. Monovalent and multivalent ligation of the B cell receptor exhibit differential dependence upon Syk and Src family kinases. Sci. Signal. 6:ra1 [Google Scholar]
  48. Qian D, Mollenauer MN, Weiss A. 48.  1996. Dominant-negative zeta-associated protein 70 inhibits T cell antigen receptor signaling. J. Exp. Med. 183:611–20 [Google Scholar]
  49. Ashe JM, Wiest DL, Abe R, Singer A. 49.  1999. ZAP-70 protein promotes tyrosine phosphorylation of T cell receptor signaling motifs (ITAMs) in immature CD4+8+ thymocytes with limiting p56lck. J. Exp. Med. 189:1163–68 [Google Scholar]
  50. Mandl JN, Monteiro JP, Vrisekoop N, Germain RN. 50.  2013. T cell-positive selection uses self-ligand binding strength to optimize repertoire recognition of foreign antigens. Immunity 38:263–74 [Google Scholar]
  51. Nakayama T, Singer A, Hsi ED, Samelson LE. 51.  1989. Intrathymic signalling in immature CD4+ CD8+ thymocytes results in tyrosine phosphorylation of the T-cell receptor zeta chain. Nature 341:651–54 [Google Scholar]
  52. Levin SE, Zhang C, Kadlecek TA, Shokat KM, Weiss A. 52.  2008. Inhibition of ZAP-70 kinase activity via an analog-sensitive allele blocks T cell receptor and CD28 superagonist signaling. J. Biol. Chem. 283:15419–30 [Google Scholar]
  53. Braiman A, Isakov N. 53.  2015. The role of Crk adaptor proteins in T-cell adhesion and migration. Front. Immunol. 6:509 [Google Scholar]
  54. Wu J, Zhao Q, Kurosaki T, Weiss A. 54.  1997. The Vav binding site (Y315) in ZAP-70 is critical for antigen receptor–mediated signal transduction. J. Exp. Med. 185:1877–82 [Google Scholar]
  55. Swat W, Fujikawa K. 55.  2005. The Vav family: at the crossroads of signaling pathways. Immunol. Res. 32:259–65 [Google Scholar]
  56. Tybulewicz VL. 56.  2005. Vav-family proteins in T-cell signalling. Curr. Opin. Immunol. 17:267–74 [Google Scholar]
  57. Aghazadeh B, Lowry WE, Huang X-Y, Rosen MK. 57.  2000. Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Cell 102:625–33 [Google Scholar]
  58. Salojin KV, Zhang J, Meagher C, Delovitch TL. 58.  2000. ZAP-70 is essential for the T cell antigen receptor-induced plasma membrane targeting of SOS and Vav in T cells. J. Biol. Chem. 275:5966–75 [Google Scholar]
  59. Straus DB, Chan AC, Patai B, Weiss A. 59.  1996. SH2 domain function is essential for the role of the Lck tyrosine kinase in T cell receptor signal transduction. J. Biol. Chem. 271:9976–81 [Google Scholar]
  60. Di Bartolo V, Mège D, Germain V, Pelosi M, Dufour E. 60.  et al. 1999. Tyrosine 319, a newly identified phosphorylation site of ZAP-70, plays a critical role in T cell antigen receptor signaling. J. Biol. Chem. 274:6285–94 [Google Scholar]
  61. Xu H, Littman DR. 61.  1993. A kinase-independent function of Lck in potentiating antigen-specific T cell activation. Cell 74:633–43 [Google Scholar]
  62. Kong G, Dalton M, Bubeck Wardenburg J, Straus D, Kurosaki T, Chan AC. 62.  1996. Distinct tyrosine phosphorylation sites in ZAP-70 mediate activation and negative regulation of antigen receptor function. Mol. Cell Biol. 16:5026–35 [Google Scholar]
  63. Rao N, Lupher ML Jr., Ota S, Reedquist KA, Druker BJ, Band H. 63.  2000. The linker phosphorylation site Tyr292 mediates the negative regulatory effect of Cbl on ZAP-70 in T cells. J. Immunol. 164:4616–26 [Google Scholar]
  64. Magnan A, Di Bartolo V, Mura AM, Boyer C, Richelme M. 64.  et al. 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. 194:491–505 [Google Scholar]
  65. Zhao Q, Weiss A. 65.  1996. Enhancement of lymphocyte responsiveness by a gain-of-function mutation of ZAP-70. Mol. Cell Biol. 16:6765–74 [Google Scholar]
  66. Lupher ML Jr., Songyang Z, Shoelson SE, Cantley LC, Band H. 66.  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. 272:33140–44 [Google Scholar]
  67. Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ. 67.  1999. Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase. Nature 398:84–90 [Google Scholar]
  68. Thien CBF, Scaife RM, Papadimitriou JM, Murphy MA, Bowtell DDL, Langdon WY. 68.  2003. A mouse with a loss-of-function mutation in the c-Cbl TKB domain shows perturbed thymocyte signaling without enhancing the activity of the ZAP-70 tyrosine kinase. J. Exp. Med. 197:503–13 [Google Scholar]
  69. Wang HY, Altman Y, Fang D, Elly C, Dai Y. 69.  et al. 2001. Cbl promotes ubiquitination of the T cell receptor zeta through an adaptor function of Zap-70. J. Biol. Chem. 276:26004–11 [Google Scholar]
  70. Myers MD, Sosinowski T, Dragone LL, White C, Band H. 70.  et al. 2006. Src-like adaptor protein regulates TCR expression on thymocytes by linking the ubiquitin ligase c-Cbl to the TCR complex. Nat. Immunol. 7:57–66 [Google Scholar]
  71. Bunnell SC, Hong DI, Kardon JR, Yamazaki T, McGlade CJ. 71.  et al. 2002. T cell receptor ligation induces the formation of dynamically regulated signaling assemblies. J. Cell Biol. 158:1263–75 [Google Scholar]
  72. Watts JD, Affolter M, Krebs DL, Wange RL, Samelson LE, Aebersold R. 72.  1994. Identification by electrospray ionization mass spectrometry of the sites of tyrosine phosphorylation induced in activated Jurkat T cells on the protein tyrosine kinase ZAP-70. J. Biol. Chem. 269:29520–29 [Google Scholar]
  73. Geahlen RL. 73.  2009. Syk and pTyr'd: signaling through the B cell antigen receptor. Biochim. Biophys. Acta 1793:1115–27 [Google Scholar]
  74. Katz ZB, Novotna L, Blount A, Lillemeier BF. 74.  2017. A cycle of Zap70 kinase activation and release from the TCR amplifies and disperses antigenic stimuli. Nat. Immunol. 18:86–95 [Google Scholar]
  75. Visperas PR, Winger JA, Horton TM, Shah NH, Aum DJ. 75.  et al. 2015. Modification by covalent reaction or oxidation of cysteine residues in the tandem-SH2 domains of ZAP-70 and Syk can block phosphopeptide binding. Biochem. J. 465:149–61 [Google Scholar]
  76. Nathan C, Cunningham-Bussel A. 76.  2013. Beyond oxidative stress: an immunologist's guide to reactive oxygen species. Nat. Rev. Immunol. 13:349–61 [Google Scholar]
  77. Reth M. 77.  2002. Hydrogen peroxide as second messenger in lymphocyte activation. Nat. Immunol. 3:1129–34 [Google Scholar]
  78. Wheeler ML, DeFranco AL. 78.  2012. Prolonged production of reactive oxygen species in response to B cell receptor stimulation promotes B cell activation and proliferation. J. Immunol. 189:4405–4416 [Google Scholar]
  79. Mikhailik A, Ford B, Keller J, Chen Y, Nassar N, Carpino N. 79.  2007. A phosphatase activity of Sts-1 contributes to the suppression of TCR signaling. Mol. Cell 27:486–97 [Google Scholar]
  80. San Luis B, Sondgeroth B, Nassar N, Carpino N. 80.  2011. Sts-2 is a phosphatase that negatively regulates zeta-associated protein (ZAP)-70 and T cell receptor signaling pathways. J. Biol. Chem. 286:15943–54 [Google Scholar]
  81. Carpino N, Turner S, Mekala D, Takahashi Y, Zang H. 81.  et al. 2004. Regulation of ZAP-70 activation and TCR signaling by two related proteins, Sts-1 and Sts-2. Immunity 20:37–46 [Google Scholar]
  82. Yang M, Chen T, Li X, Yu Z, Tang S. 82.  et al. 2015. K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation. Nat. Immunol. 16:1253–62 [Google Scholar]
  83. Naik E, Dixit VM. 83.  2016. Usp9x is required for lymphocyte activation and homeostasis through its control of ZAP70 ubiquitination and PKCβ kinase activity. J. Immunol. 196:3438–51 [Google Scholar]
  84. Singh R, Masuda ES, Payan DG. 84.  2012. Discovery and development of spleen tyrosine kinase (SYK) inhibitors. J. Med. Chem. 55:3614–43 [Google Scholar]
  85. Wange RL, Isakov N, Burke TR Jr., Otaka A, Roller PP. 85.  et al. 1995. F2(Pmp)2-TAMζ3, a novel competitive inhibitor of the binding of ZAP-70 to the T cell antigen receptor, blocks early T cell signaling. J. Biol. Chem. 270:944–48 [Google Scholar]
  86. Nishikawa K, Sawasdikosol S, Fruman DA, Lai J, Songyang Z. 86.  et al. 2000. A peptide library approach identifies a specific inhibitor for the ZAP-70 protein tyrosine kinase. Mol. Cell 6:969–74 [Google Scholar]
  87. Kaur M, Singh M, Silakari O. 87.  2014. Insight into the therapeutic aspects of ‘Zeta-Chain Associated Protein Kinase 70 kDa’ inhibitors: a review. Cell. Signal. 26:2481–92 [Google Scholar]
  88. Visperas PR, Wilson CG, Winger JA, Yan Q, Lin K. 88.  et al. 2017. Identification of inhibitors of the association of ZAP-70 with the T cell receptor by high-throughput screen. SLAS Discov 22:324–31 [Google Scholar]
  89. Bishop A, Buzko O, Heyeck-Dumas S, Jung I, Kraybill B. 89.  et al. 2000. Unnatural ligands for engineered proteins: new tools for chemical genetics. Annu. Rev. Biophys. Biomol. Struct. 29:577–606 [Google Scholar]
  90. Au-Yeung BB, Melichar HJ, Ross JO, Cheng DA, Zikherman J. 90.  et al. 2014. Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development. Nat. Immunol. 15:687–94 [Google Scholar]
  91. Jenkins MR, Stinchcombe JC, Au-Yeung BB, Asano Y, Ritter AT. 91.  et al. 2014. Distinct structural and catalytic roles for Zap70 in formation of the immunological synapse in CTL. eLife 3:e01310 [Google Scholar]
  92. Palacios EH, Weiss A. 92.  2007. Distinct roles for Syk and ZAP-70 during early thymocyte development. J. Exp. Med. 204:1703–15 [Google Scholar]
  93. Cheng AM, Negishi I, Anderson SJ, Chan AC, Bolen J. 93.  et al. 1997. The Syk and ZAP-70 SH2-containing tyrosine kinases are implicated in pre-T cell receptor signaling. PNAS 94:9797–801 [Google Scholar]
  94. Negishi I, Motoyama N, Nakayama K, Senju S, Hatakeyama S. 94.  et al. 1995. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376:435–38 [Google Scholar]
  95. Kadlecek TA, van Oers NS, Lefrancois L, Olson S, Finlay D. 95.  et al. 1998. Differential requirements for ZAP-70 in TCR signaling and T cell development. J. Immunol. 161:4688–94 [Google Scholar]
  96. Van Laethem F, Tikhonova AN, Pobezinsky LA, Tai X, Kimura MY. 96.  et al. 2013. Lck availability during thymic selection determines the recognition specificity of the T cell repertoire. Cell 154:1326–41 [Google Scholar]
  97. Liu X, Adams A, Wildt KF, Aronow B, Feigenbaum L, Bosselut R. 97.  2003. Restricting Zap70 expression to CD4+CD8+ thymocytes reveals a T cell receptor-dependent proofreading mechanism controlling the completion of positive selection. J. Exp. Med. 197:363–73 [Google Scholar]
  98. Liu X, Bosselut R. 98.  2004. Duration of TCR signaling controls CD4-CD8 lineage differentiation in vivo. Nat. Immunol. 5:280–88 [Google Scholar]
  99. Saini M, Sinclair C, Marshall D, Tolaini M, Sakaguchi S, Seddon B. 99.  2010. Regulation of Zap70 expression during thymocyte development enables temporal separation of CD4 and CD8 repertoire selection at different signaling thresholds. Sci. Signal. 3:ra23 [Google Scholar]
  100. Ross JO, Melichar HJ, Au-Yeung BB, Herzmark P, Weiss A, Robey EA. 100.  2014. Distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and T-cell receptor signaling patterns. PNAS 111:E2550–58 [Google Scholar]
  101. Sinclair C, Seddon B. 101.  2014. Overlapping and asymmetric functions of TCR signaling during thymic selection of CD4 and CD8 lineages. J. Immunol. 192:5151–59 [Google Scholar]
  102. Melichar HJ, Ross JO, Herzmark P, Hogquist KA, Robey EA. 102.  2013. Distinct temporal patterns of T cell receptor signaling during positive versus negative selection in situ. Sci. Signal. 6:ra92 [Google Scholar]
  103. Ebert PJR, Ehrlich LIR, Davis MM. 103.  2008. Low ligand requirement for deletion and lack of synapses in positive selection enforce the gauntlet of thymic T cell maturation. Immunity 29:734–45 [Google Scholar]
  104. Daniels MA, Teixeiro E, Gill J, Hausmann B, Roubaty D. 104.  et al. 2006. Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444:724–29 [Google Scholar]
  105. Zikherman J, Parameswaran R, Weiss A. 105.  2012. Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature 489:160–64 [Google Scholar]
  106. Wencker M, Turchinovich G, Di Marco Barros R, Deban L, Jandke A. 106.  et al. 2014. Innate-like T cells straddle innate and adaptive immunity by altering antigen-receptor responsiveness. Nat. Immunol. 15:80–87 [Google Scholar]
  107. Colucci F, Schweighoffer E, Tomasello E, Turner M, Ortaldo JR. 107.  et al. 2002. Natural cytotoxicity uncoupled from the Syk and ZAP-70 intracellular kinases. Nat. Immunol. 3:288–94 [Google Scholar]
  108. Schweighoffer E, Vanes L, Mathiot A, Nakamura T, Tybulewicz VLJ. 108.  2003. Unexpected requirement for ZAP-70 in pre-B cell development and allelic exclusion. Immunity 18:523–33 [Google Scholar]
  109. Schim van der Loeff I, Hsu LY, Saini M, Weiss A, Seddon B. 109.  2014. Zap70 is essential for long-term survival of naive CD8 T cells. J. Immunol. 193:2873–80 [Google Scholar]
  110. Au-Yeung BB, Zikherman J, Mueller JL, Ashouri JF, Matloubian M. 110.  et al. 2014. A sharp T-cell antigen receptor signaling threshold for T-cell proliferation. PNAS 111:E3679–88 [Google Scholar]
  111. O'Shea JJ, Paul WE. 111.  2010. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327:1098–102 [Google Scholar]
  112. Jirmanova L, Giardino Torchia ML, Sarma ND, Mittelstadt PR, Ashwell JD. 112.  2011. Lack of the T cell-specific alternative p38 activation pathway reduces autoimmunity and inflammation. Blood 118:3280–89 [Google Scholar]
  113. Tewari K, Walent J, Svaren J, Zamoyska R, Suresh M. 113.  2006. Differential requirement for Lck during primary and memory CD8+ T cell responses. PNAS 103:16388–93 [Google Scholar]
  114. Krishnan S, Warke VG, Nambiar MP, Tsokos GC, Farber DL. 114.  2003. The FcRγ subunit and Syk kinase replace the CD3ζ-chain and ZAP-70 kinase in the TCR signaling complex of human effector CD4 T cells. J. Immunol. 170:4189–95 [Google Scholar]
  115. Li MO, Rudensky AY. 115.  2016. T cell receptor signalling in the control of regulatory T cell differentiation and function. Nat. Rev. Immunol. 16:220–33 [Google Scholar]
  116. Brownlie RJ, Zamoyska R. 116.  2013. T cell receptor signalling networks: branched, diversified and bounded. Nat. Rev. Immunol. 13:257–69 [Google Scholar]
  117. Hsu LY, Tan YX, Xiao Z, Malissen M, Weiss A. 117.  2009. A hypomorphic allele of ZAP-70 reveals a distinct thymic threshold for autoimmune disease versus autoimmune reactivity. J. Exp. Med. 206:2527–41 [Google Scholar]
  118. Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. 118.  2007. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat. Immunol. 8:1353–62 [Google Scholar]
  119. Chinen T, Kannan AK, Levine AG, Fan X, Klein U. 119.  et al. 2016. An essential role for the IL-2 receptor in Treg cell function. Nat. Immunol. 17:1322–33 [Google Scholar]
  120. Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S. 120.  2008. Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. PNAS 105:10113–18 [Google Scholar]
  121. Schmidt AM, Lu W, Sindhava VJ, Huang Y, Burkhardt JK. 121.  et al. 2015. Regulatory T cells require TCR signaling for their suppressive function. J. Immunol. 194:4362–70 [Google Scholar]
  122. Levine AG, Arvey A, Jin W, Rudensky AY. 122.  2014. Continuous requirement for the TCR in regulatory T cell function. Nat. Immunol. 15:1070–78 [Google Scholar]
  123. Vahl JC, Drees C, Heger K, Heink S, Fischer JC. 123.  et al. 2014. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 41:722–36 [Google Scholar]
  124. Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE. 124.  et al. 2001. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J. Exp. Med. 194:1639–48 [Google Scholar]
  125. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D. 125.  et al. 2003. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N. Engl. J. Med. 348:1764–75 [Google Scholar]
  126. Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ. 126.  et al. 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. 351:893–901 [Google Scholar]
  127. Rassenti LZ, Jain S, Keating MJ, Wierda WG, Grever MR. 127.  et al. 2008. Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia. Blood 112:1923–30 [Google Scholar]
  128. Claus R, Lucas DM, Stilgenbauer S, Ruppert AS, Yu L. 128.  et al. 2012. Quantitative DNA methylation analysis identifies a single CpG dinucleotide important for ZAP-70 expression and predictive of prognosis in chronic lymphocytic leukemia. J. Clin. Oncol. 30:2483–91 [Google Scholar]
  129. Claus R, Lucas DM, Ruppert AS, Williams KE, Weng D. 129.  et al. 2014. Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia. Blood 124:42–48 [Google Scholar]
  130. Chen L, Widhopf G, Huynh L, Rassenti L, Rai KR. 130.  et al. 2002. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood 100:4609–14 [Google Scholar]
  131. Chen L, Apgar J, Huynh L, Dicker F, Giago-McGahan T. 131.  et al. 2005. ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia. Blood 105:2036–41 [Google Scholar]
  132. Chen L, Huynh L, Apgar J, Tang L, Rassenti L. 132.  et al. 2008. ZAP-70 enhances IgM signaling independent of its kinase activity in chronic lymphocytic leukemia. Blood 111:2685–92 [Google Scholar]
  133. Gobessi S, Laurenti L, Longo PG, Sica S, Leone G, Efremov DG. 133.  2007. ZAP-70 enhances B-cell-receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells. Blood 109:2032–39 [Google Scholar]
  134. Decker T, Schneller F, Kronschnabl M, Dechow T, Lipford GB. 134.  et al. 2000. Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells: costimulation with IL-2 results in a highly immunogenic phenotype. Exp. Hematol. 28:558–68 [Google Scholar]
  135. Wagner M, Oelsner M, Moore A, Gotte F, Kuhn PH. 135.  et al. 2016. Integration of innate into adaptive immune responses in ZAP-70-positive chronic lymphocytic leukemia. Blood 127:436–48 [Google Scholar]
  136. Richardson SJ, Matthews C, Catherwood MA, Alexander HD, Carey BS. 136.  et al. 2006. ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL). Blood 107:3584–92 [Google Scholar]
  137. Calpe E, Codony C, Baptista MJ, Abrisqueta P, Carpio C. 137.  et al. 2011. ZAP-70 enhances migration of malignant B lymphocytes toward CCL21 by inducing CCR7 expression via IgM-ERK1/2 activation. Blood 118:4401–10 [Google Scholar]
  138. Amin NA, Balasubramanian S, Saiya-Cork K, Shedden K, Hu N, Malek SN. 138.  2017. Cell-intrinsic determinants of ibrutinib-induced apoptosis in chronic lymphocytic leukemia. Clin. Cancer Res. 23:1049–59 [Google Scholar]
  139. Arpaia E, Shahar M, Dadi H, Cohen A, Roifman CM. 139.  1994. Defective T cell receptor signaling and CD8+ thymic selection in humans lacking Zap-70 kinase. Cell 76:947–58 [Google Scholar]
  140. Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL. 140.  et al. 1994. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency. Science 264:1599–601 [Google Scholar]
  141. Elder ME, Lin D, Clever J, Chan AC, Hope TJ. 141.  et al. 1994. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264:1596–99 [Google Scholar]
  142. Cuvelier GD, Rubin TS, Wall DA, Schroeder ML. 142.  2016. Long-term outcomes of hematopoietic stem cell transplantation for ZAP70 deficiency. J. Clin. Immunol. 36:713–24 [Google Scholar]
  143. Katamura K, Tai G, Tachibana T, Yamabe H, Ohmori K. 143.  et al. 1999. Existence of activated and memory CD4+ T cells in peripheral blood and their skin infiltration in CD8 deficiency. Clin. Exp. Immunol. 115:124–30 [Google Scholar]
  144. Karaca E, Karakoc-Aydiner E, Bayrak OF, Keles S, Sevli S. 144.  et al. 2013. Identification of a novel mutation in ZAP70 and prenatal diagnosis in a Turkish family with severe combined immunodeficiency disorder. Gene 512:189–93 [Google Scholar]
  145. Turul T, Tezcan I, Artac H, de Bruin-Versteeg S, Barendregt BH. 145.  et al. 2009. Clinical heterogeneity can hamper the diagnosis of patients with ZAP70 deficiency. Eur. J. Pediatr. 168:87–93 [Google Scholar]
  146. Picard C, Dogniaux S, Chemin K, Maciorowski Z, Lim A. 146.  et al. 2009. Hypomorphic mutation of ZAP70 in human results in a late onset immunodeficiency and no autoimmunity. Eur. J. Immunol. 39:1966–76 [Google Scholar]
  147. Newell A, Dadi H, Goldberg R, Ngan BY, Grunebaum E, Roifman CM. 147.  2011. Diffuse large B-cell lymphoma as presenting feature of Zap-70 deficiency. J. Allergy Clin. Immunol. 127:517–20 [Google Scholar]
  148. Poliani PL, Fontana E, Roifman CM, Notarangelo LD. 148.  2013. ζ chain-associated protein of 70 kDa (ZAP70) deficiency in human subjects is associated with abnormalities of thymic stromal cells: implications for T-cell tolerance. J. Allergy Clin. Immunol. 131:597–600.e2 [Google Scholar]
  149. Shirkani A, Shahrooei M, Azizi G, Rokni-Zadeh H, Abolhassani H. 149.  et al. 2017. Novel mutation of ZAP-70-related combined immunodeficiency: first case from the National Iranian Registry and review of the literature. Immunol. Investig. 46:70–79 [Google Scholar]
  150. Liu Q, Wang YP, Liu Q, Zhao Q, Chen XM. 150.  et al. 2017. Novel compound heterozygous mutations in ZAP70 in a Chinese patient with leaky severe combined immunodeficiency disorder. Immunogenetics 69:199–209 [Google Scholar]
  151. Akar HH, Patiroglu T, Akyildiz BN, Tekerek NU, Dogan MS. 151.  et al. 2015. Silent brain infarcts in two patients with zeta chain-associated protein 70 kDa (ZAP70) deficiency. Clin. Immunol. 158:88–91 [Google Scholar]
  152. Esenboga S, Ayvaz DC, Cetinkaya PG, van der Burg M, Tezcan İ. 152.  2016. An infant with ZAP-70 deficiency with disseminated mycobacterial disease. J. Clin. Immunol. 36:103–6 [Google Scholar]
  153. Kim VH, Murguia L, Schechter T, Grunebaum E, Roifman CM. 153.  2013. Emergency treatment for ζ chain-associated protein of 70 kDa (ZAP70) deficiency. J. Allergy Clin. Immunol. 131:1233–35 [Google Scholar]
  154. Noraz N, Schwarz K, Steinberg M, Dardalhon V, Rebouissou C. 154.  et al. 2000. Alternative antigen receptor (TCR) signaling in T cells derived from ZAP-70-deficient patients expressing high levels of Syk. J. Biol. Chem. 275:15832–38 [Google Scholar]
  155. Meinl E, Lengenfelder D, Blank N, Pirzer R, Barata L, Hivroz C. 155.  2000. Differential requirement of ZAP-70 for CD2-mediated activation pathways of mature human T cells. J. Immunol. 165:3578–83 [Google Scholar]
  156. Toyabe Si, Watanabe A, Harada W, Karasawa T, Uchiyama M. 156.  2001. Specific immunoglobulin E responses in ZAP‐70‐deficient patients are mediated by Syk‐dependent T‐cell receptor signalling. Immunology 103:164–71 [Google Scholar]
  157. Fischer A. 157.  2000. Severe combined immunodeficiencies (SCID). Clin. Exp. Immunol. 122:143–49 [Google Scholar]
  158. Hauck F, Blumenthal B, Fuchs S, Lenoir C, Martin E. 158.  et al. 2015. SYK expression endows human ZAP70-deficient CD8 T cells with residual TCR signaling. Clin. Immunol. 161:103–9 [Google Scholar]
  159. Honig M, Schuetz C, Schwarz K, Rojewski M, Jacobsen E. 159.  et al. 2012. Immunological reconstitution in a patient with ZAP-70 deficiency following transfusion of blood lymphocytes from a previously transplanted sibling without conditioning. Bone Marrow Transplant 47:305–7 [Google Scholar]
  160. Gelfand EW, Weinberg K, Mazer BD, Kadlecek TA, Weiss A. 160.  1995. Absence of ZAP-70 prevents signaling through the antigen receptor on peripheral blood T cells but not on thymocytes. J. Exp. Med. 182:1057–65 [Google Scholar]
  161. Matsuda S, Suzuki-Fujimoto T, Minowa A, Ueno H, Katamura K, Koyasu S. 161.  1999. Temperature-sensitive ZAP70 mutants degrading through a proteasome-independent pathway: restoration of a kinase domain mutant by Cdc37. J. Biol. Chem. 274:34515–18 [Google Scholar]
  162. Wiest DL, Ashe JM, Howcroft TK, Lee H-M, Kemper DM. 162.  et al. 1997. A spontaneously arising mutation in the DLAARN motif of murine ZAP-70 abrogates kinase activity and arrests thymocyte development. Immunity 6:663–71 [Google Scholar]
  163. Elder ME, Skoda-Smith S, Kadlecek TA, Wang F, Wu J, Weiss A. 163.  2001. Distinct T cell developmental consequences in humans and mice expressing identical mutations in the DLAARN motif of ZAP-70. J. Immunol. 166:656–61 [Google Scholar]
  164. Gavino C, Landekic M, Zeng J, Wu N, Jung S. 164.  et al. 2017. Morpholino-based correction of hypomorphic ZAP70 mutation in an adult with combined immunodeficiency. J. Allergy Clin. Immunol. 139:1688–92.e10 [Google Scholar]
  165. Roifman CM, Dadi H, Somech R, Nahum A, Sharfe N. 165.  2010. Characterization of ζ-associated protein, 70 kd (ZAP70)-deficient human lymphocytes. J. Allergy Clin. Immunol. 126:1226–33.e1 [Google Scholar]
  166. Chu DH, Morita CT, Weiss A. 166.  1998. The Syk family of protein tyrosine kinases in T-cell activation and development. Immunol. Rev. 165:167–80 [Google Scholar]
  167. Chu DH, van Oers NS, Malissen M, Harris J, Elder M, Weiss A. 167.  1999. Pre-T cell receptor signals are responsible for the down-regulation of Syk protein tyrosine kinase expression. J. Immunol. 163:2610–20 [Google Scholar]
  168. Sakaguchi N, Takahashi T, Hata H, Nomura T, Tagami T. 168.  et al. 2003. Altered thymic T-cell selection due to a mutation of the ZAP-70 gene causes autoimmune arthritis in mice. Nature 426:454–60 [Google Scholar]
  169. Yoshitomi H, Sakaguchi N, Kobayashi K, Brown GD, Tagami T. 169.  et al. 2005. A role for fungal β-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice. J. Exp. Med. 201:949–60 [Google Scholar]
  170. Tanaka S, Maeda S, Hashimoto M, Fujimori C, Ito Y. 170.  et al. 2010. Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function. J. Immunol. 185:2295–305 [Google Scholar]
  171. Ruutu M, Thomas G, Steck R, Degli-Esposti MA, Zinkernagel MS. 171.  et al. 2012. β-Glucan triggers spondylarthritis and Crohn's disease-like ileitis in SKG mice. Arthritis Rheumatol 64:2211–22 [Google Scholar]
  172. Sakaguchi S, Benham H, Cope AP, Thomas R. 172.  2012. T-cell receptor signaling and the pathogenesis of autoimmune arthritis: insights from mouse and man. Immunol. Cell Biol. 90:277–87 [Google Scholar]
  173. Guerard S, Boieri M, Hultqvist M, Holmdahl R, Wing K. 173.  2016. The SKG mutation in ZAP-70 also confers arthritis susceptibility in C57 black mouse strains. Scand. J. Immunol. 84:3–11 [Google Scholar]
  174. Sakaguchi S, Sakaguchi N, Yoshitomi H, Hata H, Takahashi T, Nomura T. 174.  2006. Spontaneous development of autoimmune arthritis due to genetic anomaly of T cell signal transduction: Part 1. Semin. Immunol. 18:199–206 [Google Scholar]
  175. Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T. 175.  et al. 2007. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J. Exp. Med. 204:41–47 [Google Scholar]
  176. Hashimoto M, Hirota K, Yoshitomi H, Maeda S, Teradaira S. 176.  et al. 2010. Complement drives Th17 cell differentiation and triggers autoimmune arthritis. J. Exp. Med. 207:1135–43 [Google Scholar]
  177. Benham H, Rehaume LM, Hasnain SZ, Velasco J, Baillet AC. 177.  et al. 2014. Interleukin-23 mediates the intestinal response to microbial β-1,3-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis Rheumatol 66:1755–67 [Google Scholar]
  178. Peterson LK, Shaw LA, Joetham A, Sakaguchi S, Gelfand EW, Dragone LL. 178.  2011. SLAP deficiency enhances number and function of regulatory T cells preventing chronic autoimmune arthritis in SKG mice. J. Immunol. 186:2273–81 [Google Scholar]
  179. Sood S, Brownlie RJ, Garcia C, Cowan G, Salmond RJ. 179.  et al. 2016. Loss of the protein tyrosine phosphatase PTPN22 reduces mannan-induced autoimmune arthritis in SKG mice. J. Immunol. 197:429–40 [Google Scholar]
  180. Siggs OM, Miosge LA, Yates AL, Kucharska EM, Sheahan D. 180.  et al. 2007. Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions. Immunity 27:912–26 [Google Scholar]
  181. Cauwe B, Tian L, Franckaert D, Pierson W, Staats KA. 181.  et al. 2014. A novel Zap70 mutation with reduced protein stability demonstrates the rate-limiting threshold for Zap70 in T-cell receptor signalling. Immunology 141:377–87 [Google Scholar]
  182. Jakob T, Kollisch GV, Howaldt M, Bewersdorff M, Rathkolb B. 182.  et al. 2008. Novel mouse mutants with primary cellular immunodeficiencies generated by genome-wide mutagenesis. J. Allergy Clin. Immunol. 121:179–84.e7 [Google Scholar]
  183. Siggs OM, Yates AL, Schlenner S, Liston A, Lesage S, Goodnow CC. 183.  2014. A ZAP-70 kinase domain variant prevents thymocyte-positive selection despite signalling CD69 induction. Immunology 141:587–95 [Google Scholar]
  184. Kalekar LA, Mueller DL. 184.  2017. Relationship between CD4 regulatory T cells and anergy in vivo. J. Immunol. 198:2527–33 [Google Scholar]
/content/journals/10.1146/annurev-immunol-042617-053335
Loading
/content/journals/10.1146/annurev-immunol-042617-053335
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error