1932

Abstract

T cell receptors (TCRs) are protein complexes formed by six different polypeptides. In most T cells, TCRs are composed of αβ subunits displaying immunoglobulin-like variable domains that recognize peptide antigens associated with major histocompatibility complex molecules expressed on the surface of antigen-presenting cells. TCRαβ subunits are associated with the CD3 complex formed by the γ, δ, ε, and ζ subunits, which are invariable and ensure signal transduction. Here, we review how the expression and function of TCR complexes are orchestrated by several fine-tuned cellular processes that encompass () synthesis of the subunits and their correct assembly and expression at the plasma membrane as a single functional complex, () TCR membrane localization and dynamics at the plasma membrane and in endosomal compartments, () TCR signal transduction leading to T cell activation, and () TCR degradation. These processes balance each other to ensure efficient T cell responses to a variety of antigenic stimuli while preventing autoimmunity.

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2018-04-26
2024-06-14
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Literature Cited

  1. Meuer SC, Fitzgerald KA, Hussey RE, Hodgdon JC, Schlossman SF, Reinherz EL. 1.  1983. Clonotypic structures involved in antigen-specific human T cell function. Relationship to the T3 molecular complex. J. Exp. Med. 157:705–19 [Google Scholar]
  2. Haskins K, Kubo R, White J, Pigeon M, Kappler J, Marrack P. 2.  1983. The major histocompatibility complex-restricted antigen receptor on T cells: I. Isolation with a monoclonal antibody. J. Exp. Med. 157:1149–69 [Google Scholar]
  3. Samelson LE, Germain RN, Schwartz RH. 3.  1983. Monoclonal antibodies against the antigen receptor on a cloned T-cell hybrid. PNAS 80:6972–76 [Google Scholar]
  4. Allison JP, McIntyre BW, Bloch D. 4.  1982. Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody. J. Immunol. 129:2293–300 [Google Scholar]
  5. Reinherz EL. 5.  2014. Revisiting the discovery of the αβ TCR complex and its co-receptors. Front. Immunol. 5:583 [Google Scholar]
  6. Meuer SC, Acuto O, Hussey RE, Hodgdon JC, Fitzgerald KA. 6.  et al. 1983. Evidence for the T3-associated 90K heterodimer as the T-cell antigen receptor. Nature 303:808–10 [Google Scholar]
  7. Allison JP, Lanier LL. 7.  1985. Identification of antigen receptor-associated structures on murine T cells. Nature 314:107–9 [Google Scholar]
  8. Oettgen HC, Pettey CL, Maloy WL, Terhorst C. 8.  1986. A T3-like protein complex associated with the antigen receptor on murine T cells. Nature 320:272–75 [Google Scholar]
  9. Meuer SC, Hodgdon JC, Hussey RE, Protentis JP, Schlossman SF, Reinherz EL. 9.  1983. Antigen-like effects of monoclonal antibodies directed at receptors on human T cell clones. J. Exp. Med. 158:988–95 [Google Scholar]
  10. Kaye J, Porcelli S, Tite J, Jones B, Janeway CA Jr. 10.  1983. Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells. J. Exp. Med. 158:836–56 [Google Scholar]
  11. Acuto O, Meuer SC, Hodgdon JC, Schlossman SF, Reinherz EL. 11.  1983. Peptide variability exists within α and β subunits of the T cell receptor for antigen. J. Exp. Med. 158:1368–73 [Google Scholar]
  12. Fabbi M, Acuto O, Smart JE, Reinherz EL. 12.  1984. Homology of Ti α-subunit of a T-cell antigen-MHC receptor with immunoglobulin. Nature 312:269–71 [Google Scholar]
  13. Hedrick SM, Cohen DI, Nielsen EA, Davis MM. 13.  1984. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature 308:149–53 [Google Scholar]
  14. Hedrick SM, Nielsen EA, Kavaler J, Cohen DI, Davis MM. 14.  1984. Sequence relationships between putative T-cell receptor polypeptides and immunoglobulins. Nature 308:153–58 [Google Scholar]
  15. Royer HD, Acuto O, Fabbi M, Tizard R, Ramachandran K. 15.  et al. 1984. Genes encoding the Ti β subunit of the antigen/MHC receptor undergo rearrangement during intrathymic ontogeny prior to surface T3-Ti expression. Cell 39:261–66 [Google Scholar]
  16. Yanagi Y, Yoshikai Y, Leggett K, Clark SP, Aleksander I, Mak TW. 16.  1984. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature 308:145–49 [Google Scholar]
  17. Saito H, Kranz DM, Takagaki Y, Hayday AC, Eisen HN, Tonegawa S. 17.  1984. Complete primary structure of a heterodimeric T-cell receptor deduced from cDNA sequences. Nature 309:757–62 [Google Scholar]
  18. Saito H, Kranz DM, Takagaki Y, Hayday AC, Eisen HN, Tonegawa S. 18.  1984. A third rearranged and expressed gene in a clone of cytotoxic T lymphocytes. Nature 312:36–40 [Google Scholar]
  19. Chien Y, Becker DM, Lindsten T, Okamura M, Cohen DI, Davis MM. 19.  1984. A third type of murine T-cell receptor gene. Nature 312:31–35 [Google Scholar]
  20. Brenner MB, McLean J, Dialynas DP, Strominger JL, Smith JA. 20.  et al. 1986. Identification of a putative second T-cell receptor. Nature 322:145–49 [Google Scholar]
  21. Chien YH, Iwashima M, Kaplan KB, Elliott JF, Davis MM. 21.  1987. A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation. Nature 327:677–82 [Google Scholar]
  22. Davis MM, Chien YH. 22.  2013. T-cell antigen receptors. Fundamental Immunology WE Paul 279–310 Philadelphia: Lippincot Williams Wilkins, 7th ed.. [Google Scholar]
  23. Vantourout P, Hayday A. 23.  2013. Six-of-the-best: unique contributions of γδ T cells to immunology. Nat. Rev. Immunol. 13:88–100 [Google Scholar]
  24. Krissansen GW, Owen MJ, Verbi W, Crumpton MJ. 24.  1986. Primary structure of the T3 γ subunit of the T3/T cell antigen receptor complex deduced from cDNA sequences: evolution of the T3 γ and δ subunits. EMBO J 5:1799–808 [Google Scholar]
  25. van den Elsen P, Shepley BA, Borst J, Coligan JE, Markham AF. 25.  et al. 1984. Isolation of cDNA clones encoding the 20K T3 glycoprotein of human T-cell receptor complex. Nature 312:413–18 [Google Scholar]
  26. Gold DP, Puck JM, Pettey CL, Cho M, Coligan J. 26.  et al. 1986. Isolation of cDNA clones encoding the 20K non-glycosylated polypeptide chain of the human T-cell receptor/T3 complex. Nature 321:431–34 [Google Scholar]
  27. Tunnacliffe A, Buluwela L, Rabbitts TH. 27.  1987. Physical linkage of three CD3 genes on human chromosome 11. EMBO J 6:2953–57 [Google Scholar]
  28. Tunnacliffe A, Olsson C, Buluwela L, Rabbitts TH. 28.  1988. Organization of the human CD3 locus on chromosome 11. Eur. J. Immunol. 18:1639–42 [Google Scholar]
  29. Weissman AM, Baniyash M, Hou D, Samelson LE, Burgess WH, Klausner RD. 29.  1988. Molecular cloning of the zeta chain of the T cell antigen receptor. Science 239:1018–21 [Google Scholar]
  30. Clayton LK, D'Adamio L, Howard FD, Sieh M, Hussey RE. 30.  et al. 1991. CD3η and CD3ζ are alternatively spliced products of a common genetic locus and are transcriptionally and/or post-transcriptionally regulated during T-cell development. PNAS 88:5202–6 [Google Scholar]
  31. Huppa JB, Axmann M, Mortelmaier MA, Lillemeier BF, Newell EW. 31.  et al. 2010. TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity. Nature 463:963–67 [Google Scholar]
  32. Krogsgaard M, Li QJ, Sumen C, Huppa JB, Huse M, Davis MM. 32.  2005. Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity. Nature 434:238–43 [Google Scholar]
  33. Lillemeier BF, Mortelmaier MA, Forstner MB, Huppa JB, Groves JT, Davis MM. 33.  2010. TCR and Lat are expressed on separate protein islands on T cell membranes and concatenate during activation. Nat. Immunol. 11:90–96 [Google Scholar]
  34. Lillemeier BF, Pfeiffer JR, Surviladze Z, Wilson BS, Davis MM. 34.  2006. Plasma membrane-associated proteins are clustered into islands attached to the cytoskeleton. PNAS 103:18992–97 [Google Scholar]
  35. Schamel WW, Alarcón B. 35.  2013. Organization of the resting TCR in nanoscale oligomers. Immunol. Rev. 251:13–20 [Google Scholar]
  36. Schamel WW, Arechaga I, Risueno RM, van Santen HM, Cabezas P. 36.  et al. 2005. Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response. J. Exp. Med. 202:493–503 [Google Scholar]
  37. Clevers H, Alarcón B, Wileman T, Terhorst C. 37.  1988. The T cell receptor/CD3 complex: a dynamic protein ensemble. Annu. Rev. Immunol. 6:629–62 [Google Scholar]
  38. Klausner RD, Lippincott-Schwartz J, Bonifacino JS. 38.  1990. The T cell antigen receptor: insights into organelle biology. Annu. Rev. Cell Biol. 6:403–31 [Google Scholar]
  39. Orloff DG, Ra CS, Frank SJ, Klausner RD, Kinet JP. 39.  1990. Family of disulphide-linked dimers containing the ζ and η chains of the T-cell receptor and the γ chain of Fc receptors. Nature 347:189–91 [Google Scholar]
  40. Reth M. 40.  1989. Antigen receptor tail clue. Nature 338:383–84 [Google Scholar]
  41. Arechaga I, Swamy M, Abia D, Schamel WA, Alarcón B, Valpuesta JM. 41.  2010. Structural characterization of the TCR complex by electron microscopy. Int. Immunol. 22:897–903 [Google Scholar]
  42. Khan JM, Cheruku HR, Tong JC, Ranganathan S. 42.  2011. MPID-T2: a database for sequence-structure-function analyses of pMHC and TR/pMHC structures. Bioinformatics 27:1192–93 [Google Scholar]
  43. Arnett KL, Harrison SC, Wiley DC. 43.  2004. Crystal structure of a human CD3-ε/δ dimer in complex with a UCHT1 single-chain antibody fragment. PNAS 101:16268–73 [Google Scholar]
  44. Call ME, Schnell JR, Xu C, Lutz RA, Chou JJ, Wucherpfennig KW. 44.  2006. The structure of the ζζ transmembrane dimer reveals features essential for its assembly with the T cell receptor. Cell 127:355–68 [Google Scholar]
  45. Sun ZY, Kim ST, Kim IC, Fahmy A, Reinherz EL, Wagner G. 45.  2004. Solution structure of the CD3εδ ectodomain and comparison with CD3εγ as a basis for modeling T cell receptor topology and signaling. PNAS 101:16867–72 [Google Scholar]
  46. Xu C, Gagnon E, Call ME, Schnell JR, Schwieters CD. 46.  et al. 2008. Regulation of T cell receptor activation by dynamic membrane binding of the CD3ε cytoplasmic tyrosine-based motif. Cell 135:702–13 [Google Scholar]
  47. Stone JD, Chervin AS, Kranz DM. 47.  2009. T-cell receptor binding affinities and kinetics: impact on T-cell activity and specificity. Immunology 126:165–76 [Google Scholar]
  48. Natarajan K, McShan AC, Jiang J, Kumirov VK, Wang R. 48.  et al. 2017. An allosteric site in the T-cell receptor Cβ domain plays a critical signalling role. Nat. Commun. 8:15260 [Google Scholar]
  49. Reiser JB, Gregoire C, Darnault C, Mosser T, Guimezanes A. 49.  et al. 2002. A T cell receptor CDR3β loop undergoes conformational changes of unprecedented magnitude upon binding to a peptide/MHC class I complex. Immunity 16:345–54 [Google Scholar]
  50. Rudolph MG, Stanfield RL, Wilson IA. 50.  2006. How TCRs bind MHCs, peptides, and coreceptors. Annu. Rev. Immunol. 24:419–66 [Google Scholar]
  51. Adams JJ, Narayanan S, Liu B, Birnbaum ME, Kruse AC. 51.  et al. 2011. T cell receptor signaling is limited by docking geometry to peptide-major histocompatibility complex. Immunity 35:681–93 [Google Scholar]
  52. Wang JH, Reinherz EL. 52.  2012. The structural basis of αβ T-lineage immune recognition: TCR docking topologies, mechanotransduction, and co-receptor function. Immunol. Rev. 250:102–19 [Google Scholar]
  53. Sun ZJ, Kim KS, Wagner G, Reinherz EL. 53.  2001. Mechanisms contributing to T cell receptor signaling and assembly revealed by the solution structure of an ectodomain fragment of the CD3εγ heterodimer. Cell 105:913–23 [Google Scholar]
  54. Kim ST, Takeuchi K, Sun ZY, Touma M, Castro CE. 54.  et al. 2009. The αβ T cell receptor is an anisotropic mechanosensor. J. Biol. Chem. 284:31028–37 [Google Scholar]
  55. Kuhns MS, Girvin AT, Klein LO, Chen R, Jensen KD. 55.  et al. 2010. Evidence for a functional sidedness to the αβTCR. PNAS 107:5094–99 [Google Scholar]
  56. Blanco R, Borroto A, Schamel W, Pereira P, Alarcón B. 56.  2014. Conformational changes in the T cell receptor differentially determine T cell subset development in mice. Sci. Signal. 7:ra115 [Google Scholar]
  57. Martínez-Martín N, Risueño RM, Morreale A, Zaldívar I, Fernández-Arenas E. 57.  et al. 2009. Cooperativity between T cell receptor complexes revealed by conformational mutants of CD3ε. Sci. Signal. 2:ra43 [Google Scholar]
  58. Brazin KN, Mallis RJ, Li C, Keskin DB, Arthanari H. 58.  et al. 2014. Constitutively oxidized CXXC motifs within the CD3 heterodimeric ectodomains of the T cell receptor complex enforce the conformation of juxtaposed segments. J. Biol. Chem. 289:18880–92 [Google Scholar]
  59. Borroto A, Jiménez MA, Alarcón B, Rico M. 59.  1997. 1H-NMR analysis of CD3-ε reveals the presence of turn-helix structures around the ITAM motif in an otherwise random coil cytoplasmic tail. Biopolymers 42:75–88 [Google Scholar]
  60. Wucherpfennig KW, Gagnon E, Call MJ, Huseby ES, Call ME. 60.  2010. Structural biology of the T-cell receptor: insights into receptor assembly, ligand recognition, and initiation of signaling. Cold Spring Harb. Perspect. Biol. 2:a005140 [Google Scholar]
  61. Lippincott-Schwartz J, Bonifacino JS, Yuan LC, Klausner RD. 61.  1988. Degradation from the endoplasmic reticulum: disposing of newly synthesized proteins. Cell 54:209–20 [Google Scholar]
  62. Bonifacino JS, Suzuki CK, Klausner RD. 62.  1990. A peptide sequence confers retention and rapid degradation in the endoplasmic reticulum. Science 247:79–82 [Google Scholar]
  63. Lee SJ. 63.  1998. Endoplasmic reticulum retention and degradation of T cell antigen receptor beta chain. Exp. Mol. Med. 30:159–64 [Google Scholar]
  64. Mallabiabarrena A, Fresno M, Alarcón B. 64.  1992. An endoplasmic reticulum retention signal in the CD3 epsilon chain of the T-cell receptor. Nature 357:593–96 [Google Scholar]
  65. Mallabiabarrena A, Jiménez MA, Rico M, Alarcón B. 65.  1995. A tyrosine-containing motif mediates ER retention of CD3-ε and adopts a helix–turn structure. EMBO J 14:2257–68 [Google Scholar]
  66. Delgado P, Alarcón B. 66.  2005. An orderly inactivation of intracellular retention signals controls surface expression of the T cell antigen receptor. J. Exp. Med. 201:555–66 [Google Scholar]
  67. Minami Y, Weissman AM, Samelson LE, Klausner RD. 67.  1987. Building a multichain receptor: synthesis, degradation, and assembly of the T-cell antigen receptor. PNAS 84:2688–92 [Google Scholar]
  68. Bonifacino JS, Cosson P, Klausner RD. 68.  1990. Colocalized transmembrane determinants for ER degradation and subunit assembly explain the intracellular fate of TCR chains. Cell 63:503–13 [Google Scholar]
  69. Bonifacino JS, Cosson P, Shah N, Klausner RD. 69.  1991. Role of potentially charged transmembrane residues in targeting proteins for retention and degradation within the endoplasmic reticulum. EMBO J 10:2783–93 [Google Scholar]
  70. Letourneur F, Klausner RD. 70.  1992. A novel di-leucine motif and a tyrosine-based motif independently mediate lysosomal targeting and endocytosis of CD3 chains. Cell 69:1143–57 [Google Scholar]
  71. Alarcón B, Berkhout B, Breitmeyer J, Terhorst C. 71.  1988. Assembly of the human T cell receptor-CD3 complex takes place in the endoplasmic reticulum and involves intermediary complexes between the CD3-γδε core and single T cell receptor α or β chains. J. Biol. Chem. 263:2953–61 [Google Scholar]
  72. Weissman AM, Frank SJ, Orloff DG, Mercep M, Ashwell JD, Klausner RD. 72.  1989. Role of the zeta chain in the expression of the T cell antigen receptor: genetic reconstitution studies. EMBO J 8:3651–56 [Google Scholar]
  73. Sussman JJ, Bonifacino JS, Lippincott-Schwartz J, Weissman AM, Saito T. 73.  et al. 1988. Failure to synthesize the T cell CD3-ζ chain: structure and function of a partial T cell receptor complex. Cell 52:85–95 [Google Scholar]
  74. Ono S, Ohno H, Saito T. 74.  1995. Rapid turnover of the CD3ζ chain independent of the TCR-CD3 complex in normal T cells. Immunity 2:639–44 [Google Scholar]
  75. D'Oro U, Munitic I, Chacko G, Karpova T, McNally J, Ashwell JD. 75.  2002. Regulation of constitutive TCR internalization by the ζ-chain. J. Immunol. 169:6269–78 [Google Scholar]
  76. Alcover A, Mariuzza RA, Ermonval M, Acuto O. 76.  1990. Lysine 271 in the transmembrane domain of the T-cell antigen receptor β chain is necessary for its assembly with the CD3 complex but not for α/β dimerization. J. Biol. Chem. 265:4131–35 [Google Scholar]
  77. Cosson P, Lankford SP, Bonifacino JS, Klausner RD. 77.  1991. Membrane protein association by potential intramembrane charge pairs. Nature 351:414–16 [Google Scholar]
  78. Call ME, Pyrdol J, Wiedmann M, Wucherpfennig KW. 78.  2002. The organizing principle in the formation of the T cell receptor-CD3 complex. Cell 111:967–79 [Google Scholar]
  79. Alarcón B, Ley SC, Sánchez-Madrid F, Blumberg RS, Ju ST. 79.  et al. 1991. The CD3-γ and CD3-δ subunits of the T cell antigen receptor can be expressed within distinct functional TCR/CD3 complexes. EMBO J 10:903–12 [Google Scholar]
  80. Pérez-Aciego P, Alarcón B, Arnaiz-Villena A, Terhorst C, Timón M. 80.  et al. 1991. Expression and function of a variant T cell receptor complex lacking CD3-γ. J. Exp. Med. 174:319–26 [Google Scholar]
  81. Siegers GM, Swamy M, Fernandez-Malave E, Minguet S, Rathmann S. 81.  et al. 2007. Different composition of the human and the mouse γδ T cell receptor explains different phenotypes of CD3γ and CD3δ immunodeficiencies. J. Exp. Med. 204:2537–44 [Google Scholar]
  82. Exley M, Wileman T, Mueller B, Terhorst C. 82.  1995. Evidence for multivalent structure of T-cell antigen receptor complex. Mol. Immunol. 32:829–39 [Google Scholar]
  83. Fernández-Miguel G, Alarcón B, Iglesias A, Bluethmann H, Alvarez-Mon M. 83.  et al. 1999. Multivalent structure of an αβT cell receptor. PNAS 96:1547–52 [Google Scholar]
  84. Balagopalan L, Sherman E, Barr VA, Samelson LE. 84.  2011. Imaging techniques for assaying lymphocyte activation in action. Nat. Rev. Immunol. 11:21–33 [Google Scholar]
  85. Kumar R, Ferez M, Swamy M, Arechaga I, Rejas MT. 85.  et al. 2011. Increased sensitivity of antigen-experienced T cells through the enrichment of oligomeric T cell receptor complexes. Immunity 35:375–87 [Google Scholar]
  86. Jung Y, Riven I, Feigelson SW, Kartvelishvily E, Tohya K. 86.  et al. 2016. Three-dimensional localization of T-cell receptors in relation to microvilli using a combination of superresolution microscopies. PNAS 113:E5916–24 [Google Scholar]
  87. Blanco R, Alarcón B. 87.  2012. TCR nanoclusters as the framework for transmission of conformational changes and cooperativity. Front. Immunol. 3:115 [Google Scholar]
  88. Castro M, van Santen HM, Férez M, Alarcón B, Lythe G, Molina-París C. 88.  2014. Receptor pre-clustering and T cell responses: insights into molecular mechanisms. Front. Immunol. 5:132 [Google Scholar]
  89. Campi G, Varma R, Dustin ML. 89.  2005. Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. J. Exp. Med. 202:1031–36 [Google Scholar]
  90. Yokosuka T, Sakata-Sogawa K, Kobayashi W, Hiroshima M, Hashimoto-Tane A. 90.  et al. 2005. Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nat. Immunol. 6:1253–62 [Google Scholar]
  91. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS. 91.  et al. 1999. The immunological synapse: a molecular machine controlling T cell activation. Science 285:221–27 [Google Scholar]
  92. Monks CR, Freiberg BA, Kupfer H, Sciaky N, Kupfer A. 92.  1998. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395:82–86 [Google Scholar]
  93. Roumier A, Olivo-Marin JC, Arpin M, Michel F, Martin M. 93.  et al. 2001. The membrane-microfilament linker ezrin is involved in the formation of the immunological synapse and in T cell activation. Immunity 15:715–28 [Google Scholar]
  94. Varma R, Campi G, Yokosuka T, Saito T, Dustin ML. 94.  2006. T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25:117–27 [Google Scholar]
  95. Vardhana S, Choudhuri K, Varma R, Dustin ML. 95.  2010. Essential role of ubiquitin and TSG101 protein in formation and function of the central supramolecular activation cluster. Immunity 32:531–40 [Google Scholar]
  96. Choudhuri K, Llodra J, Roth EW, Tsai J, Gordo S. 96.  et al. 2014. Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 507:118–23 [Google Scholar]
  97. Lee KH, Dinner AR, Tu C, Campi G, Raychaudhuri S. 97.  et al. 2003. The immunological synapse balances T cell receptor signaling and degradation. Science 302:1218–22 [Google Scholar]
  98. Cemerski S, Das J, Giurisato E, Markiewicz MA, Allen PM. 98.  et al. 2008. The balance between T cell receptor signaling and degradation at the center of the immunological synapse is determined by antigen quality. Immunity 29:414–22 [Google Scholar]
  99. Cemerski S, Das J, Locasale J, Arnold P, Giurisato E. 99.  et al. 2007. The stimulatory potency of T cell antigens is influenced by the formation of the immunological synapse. Immunity 26:345–55 [Google Scholar]
  100. Niedergang F, Hemar A, Hewitt CR, Owen MJ, Dautry-Varsat A, Alcover A. 100.  1995. The Staphylococcus aureus enterotoxin B superantigen induces specific T cell receptor down-regulation by increasing its internalization. J. Biol. Chem. 270:12839–45 [Google Scholar]
  101. Liu H, Rhodes M, Wiest DL, Vignali DAA. 101.  2000. On the dynamics of TCR:CD3 complex cell surface expression and downmodulation. Immunity 13:665–75 [Google Scholar]
  102. Krangel MS. 102.  1987. Endocytosis and recycling of the T3-T cell receptor complex: the role of T3 phosphorylation. J. Exp. Med. 165:1141–59 [Google Scholar]
  103. Alcover A, Alarcón B. 103.  2000. Internalization and intracellular fate of TCR-CD3 complexes. Crit. Rev. Immunol. 20:325–46 [Google Scholar]
  104. Dietrich J, Backstrom T, Lauritsen JP, Kastrup J, Christensen MD. 104.  et al. 1998. The phosphorylation state of CD3γ influences T cell responsiveness and controls T cell receptor cycling. J. Biol. Chem. 273:24232–38 [Google Scholar]
  105. Dietrich J, Hou X, Wegener AM, Geisler C. 105.  1994. CD3 gamma contains a phosphoserine-dependent di-leucine motif involved in down-regulation of the T cell receptor. EMBO J 13:2156–66 [Google Scholar]
  106. Dietrich J, Kastrup J, Nielsen BL, Odum N, Geisler C. 106.  1997. Regulation and function of the CD3γ DxxxLL motif: a binding site for adaptor protein-1 and adaptor protein-2 in vitro. J. Cell Biol. 138:271–81 [Google Scholar]
  107. Szymczak AL, Vignali DA. 107.  2005. Plasticity and rigidity in adaptor protein-2-mediated internalization of the TCR:CD3 complex. J. Immunol. 174:4153–60 [Google Scholar]
  108. Lauritsen JP, Bonefeld CM, von Essen M, Nielsen MW, Rasmussen AB. 108.  et al. 2004. Masking of the CD3γ di-leucine-based motif by ζ is required for efficient T-cell receptor expression. Traffic 5:672–84 [Google Scholar]
  109. Das V, Nal B, Dujeancourt A, Thoulouze MI, Galli T. 109.  et al. 2004. Activation-induced polarized recycling targets T cell antigen receptors to the immunological synapse; involvement of SNARE complexes. Immunity 20:577–88 [Google Scholar]
  110. Soares H, Henriques R, Sachse M, Ventimiglia L, Alonso MA. 110.  et al. 2013. Regulated vesicle fusion generates signaling nanoterritories that control T cell activation at the immunological synapse. J. Exp. Med. 210:2415–33 [Google Scholar]
  111. Finetti F, Paccani SR, Riparbelli MG, Giacomello E, Perinetti G. 111.  et al. 2009. Intraflagellar transport is required for polarized recycling of the TCR/CD3 complex to the immune synapse. Nat. Cell Biol. 11:1332–39 [Google Scholar]
  112. Finetti F, Patrussi L, Galgano D, Cassioli C, Perinetti G. 112.  et al. 2015. The small GTPase Rab8 interacts with VAMP-3 to regulate the delivery of recycling T-cell receptors to the immune synapse. J. Cell Sci. 128:2541–52 [Google Scholar]
  113. Krummel MF, Sjaastad MD, Wulfing C, Davis MM. 113.  2000. Differential clustering of CD4 and CD3ζ during T cell recognition. Science 289:1349–52 [Google Scholar]
  114. Blanchard N, Di Bartolo V, Hivroz C. 114.  2002. In the immune synapse, ZAP-70 controls T cell polarization and recruitment of signaling proteins but not formation of the synaptic pattern. Immunity 17:389–99 [Google Scholar]
  115. Martín-Cófreces NB, Baixauli F, López MJ, Gil D, Monjas A. 115.  et al. 2012. End-binding protein 1 controls signal propagation from the T cell receptor. EMBO J 31:4140–52 [Google Scholar]
  116. Blas-Rus N, Bustos-Moran E, Perez de Castro I, de Carcer G, Borroto A. 116.  et al. 2016. Aurora A drives early signalling and vesicle dynamics during T-cell activation. Nat. Commun. 7:11389 [Google Scholar]
  117. Larghi P, Williamson DJ, Carpier JM, Dogniaux S, Chemin K. 117.  et al. 2013. VAMP7 controls T cell activation by regulating the recruitment and phosphorylation of vesicular Lat at TCR-activation sites. Nat. Immunol. 14:723–31 [Google Scholar]
  118. Purbhoo MA, Liu H, Oddos S, Owen DM, Neil MA. 118.  et al. 2010. Dynamics of subsynaptic vesicles and surface microclusters at the immunological synapse. Sci. Signal. 3:ra36 [Google Scholar]
  119. Bouchet J, Del Río-Iñiguez I, Vázquez-Chávez E, Lasserre R, Agüera-González S. 119.  et al. 2017. Rab11-FIP3 regulation of Lck endosomal traffic controls TCR signal transduction. J. Immunol. 198:2967–78 [Google Scholar]
  120. Valitutti S, Müller S, Salio M, Lanzavecchia A. 120.  1997. Degradation of T cell receptor (TCR)–CD3-ζ complexes after antigenic stimulation. J. Exp. Med. 185:1859–64 [Google Scholar]
  121. Luton F, Buferne M, Legendre V, Chauvet E, Boyer C, Schmitt-Verhulst AM. 121.  1997. Role of CD3γ and CD3δ cytoplasmic domains in cytolytic T lymphocyte functions and TCR/CD3 down-modulation. J. Immunol. 158:4162–70 [Google Scholar]
  122. Niedergang F, Dautry-Varsat A, Alcover A. 122.  1997. Peptide antigen or superantigen-induced down-regulation of TCRs involves both stimulated and unstimulated receptors. J. Immunol. 159:1703–10 [Google Scholar]
  123. San José E, Borroto A, Niedergang F, Alcover A, Alarcón B. 123.  2000. Triggering the TCR complex causes the downregulation of nonengaged receptors by a signal transduction-dependent mechanism. Immunity 12:161–70 [Google Scholar]
  124. Monjas A, Alcover A, Alarcón B. 124.  2004. Engaged and bystander T cell receptors are down-modulated by different endocytotic pathways. J. Biol. Chem. 279:55376–84 [Google Scholar]
  125. Kuhns MS, Girvin AT, Klein LO, Chen R, Jensen KD. 125.  et al. 2010. Evidence for a functional sidedness to the αβTCR. PNAS 107:5094–99 [Google Scholar]
  126. Niedergang F, Dautry-Varsat A, Alcover A. 126.  1998. Cooperative activation of TCRs by enterotoxin superantigens. J. Immunol. 161:6054–8 [Google Scholar]
  127. Fernández-Arenas E, Calleja E, Martínez-Martín N, Gharbi SI, Navajas R. 127.  et al. 2014. β-Arrestin-1 mediates the TCR-triggered re-routing of distal receptors to the immunological synapse by a PKC-mediated mechanism. EMBO J 33:559–77 [Google Scholar]
  128. Martínez-Martín N, Fernández-Arenas E, Cemerski S, Delgado P, Turner M. 128.  et al. 2011. T cell receptor internalization from the immunological synapse is mediated by TC21 and RhoG GTPase-dependent phagocytosis. Immunity 35:208–22 [Google Scholar]
  129. Luton F, Buferne M, Davoust J, Schmitt-Verhulst AM, Boyer C. 129.  1994. Evidence for protein tyrosine kinase involvement in ligand-induced TCR/CD3 internalization and surface redistribution. J. Immunol. 153:63–72 [Google Scholar]
  130. D'Oro U, Vacchio MS, Weissman AM, Ashwell JD. 130.  1997. Activation of the Lck tyrosine kinase targets cell surface T cell antigen receptors for lysosomal degradation. Immunity 7:619–28 [Google Scholar]
  131. San Jose E, Alarcón B. 131.  1999. Receptor engagement transiently diverts the T cell receptor heterodimer from a constitutive degradation pathway. J. Biol. Chem. 274:33740–46 [Google Scholar]
  132. Kishimoto H, Kubo RT, Yorifuji H, Nakayama T, Asano Y, Tada T. 132.  1995. Physical dissociation of the TCR-CD3 complex accompanies receptor ligation. J. Exp. Med. 182:1997–2006 [Google Scholar]
  133. La Gruta NL, Liu H, Dilioglou S, Rhodes M, Wiest DL, Vignali DA. 133.  2004. Architectural changes in the TCR:CD3 complex induced by MHC:peptide ligation. J. Immunol. 172:3662–69 [Google Scholar]
  134. Blanchard N, Lankar D, Faure F, Regnault A, Dumont C. 134.  et al. 2002. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/ζ complex. J. Immunol. 168:3235–41 [Google Scholar]
  135. Soares H, Lasserre R, Alcover A. 135.  2013. Orchestrating cytoskeleton and intracellular vesicle traffic to build functional immunological synapses. Immunol. Rev. 256:118–32 [Google Scholar]
  136. Baixauli F, Martín-Cófreces NB, Morlino G, Carrasco YR, Calabia-Linares C. 136.  et al. 2011. The mitochondrial fission factor dynamin-related protein 1 modulates T-cell receptor signalling at the immune synapse. EMBO J 30:1238–50 [Google Scholar]
  137. Martín-Cófreces NB, Baixauli F, Sánchez-Madrid F. 137.  2014. Immune synapse: conductor of orchestrated organelle movement. Trends Cell Biol 24:61–72 [Google Scholar]
  138. Kupfer A, Dennert G. 138.  1984. Reorientation of the microtubule-organizing center and the Golgi apparatus in cloned cytotoxic lymphocytes triggered by binding to lysable target cells. J. Immunol. 133:2762–66 [Google Scholar]
  139. Ritter AT, Asano Y, Stinchcombe JC, Dieckmann NM, Chen BC. 139.  et al. 2015. Actin depletion initiates events leading to granule secretion at the immunological synapse. Immunity 42:864–76 [Google Scholar]
  140. de la Roche M, Asano Y, Griffiths GM. 140.  2016. Origins of the cytolytic synapse. Nat. Rev. Immunol. 16:421–32 [Google Scholar]
  141. van der Merwe PA, Dushek O. 141.  2011. Mechanisms for T cell receptor triggering. Nat. Rev. Immunol. 11:47–55 [Google Scholar]
  142. Chakraborty AK, Weiss A. 142.  2014. Insights into the initiation of TCR signaling. Nat. Immunol. 15:798–807 [Google Scholar]
  143. Malissen B, Bongrand P. 143.  2015. Early T cell activation: integrating biochemical, structural, and biophysical cues. Annu. Rev. Immunol. 33:539–61 [Google Scholar]
  144. Kjer-Nielsen L, Clements CS, Purcell AW, Brooks AG, Whisstock JC. 144.  et al. 2003. A structural basis for the selection of dominant αβ T cell receptors in antiviral immunity. Immunity 18:53–64 [Google Scholar]
  145. Beddoe T, Chen Z, Clements CS, Ely LK, Bushell SR. 145.  et al. 2009. Antigen ligation triggers a conformational change within the constant domain of the αβ T cell receptor. Immunity 30:777–88 [Google Scholar]
  146. Gil D, Schamel WW, Montoya M, Sánchez-Madrid F, Alarcón B. 146.  2002. Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell 109:901–12 [Google Scholar]
  147. Aivazian D, Stern LJ. 147.  2000. Phosphorylation of T cell receptor zeta is regulated by a lipid dependent folding transition. Nat. Struct. Biol. 7:1023–6 [Google Scholar]
  148. Risueno RM, Schamel WW, Alarcón B. 148.  2008. T cell receptor engagement triggers its CD3epsilon and CD3zeta subunits to adopt a compact, locked conformation. PLOS ONE 3:e1747 [Google Scholar]
  149. Brazin KN, Mallis RJ, Das DK, Feng Y, Hwang W. 149.  et al. 2015. Structural features of the αβTCR mechanotransduction apparatus that promote pMHC discrimination. Front. Immunol. 6:441 [Google Scholar]
  150. Nika K, Soldani C, Salek M, Paster W, Gray A. 150.  et al. 2010. Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity 32:766–77 [Google Scholar]
  151. Barber EK, Dasgupta JD, Schlossman SF, Trevillyan JM, Rudd CE. 151.  1989. The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex. PNAS 86:3277–81 [Google Scholar]
  152. Turner JM, Brodsky MH, Irving BA, Levin SD, Perlmutter RM, Littman DR. 152.  1990. Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs. Cell 60:755–65 [Google Scholar]
  153. Li QJ, Dinner AR, Qi S, Irvine DJ, Huppa JB. 153.  et al. 2004. CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse. Nat. Immunol. 5:791–99 [Google Scholar]
  154. Roh KH, Lillemeier BF, Wang F, Davis MM. 154.  2015. The coreceptor CD4 is expressed in distinct nanoclusters and does not colocalize with T-cell receptor and active protein tyrosine kinase p56lck. PNAS 112:E1604–13 [Google Scholar]
  155. Drevot P, Langlet C, Guo XJ, Bernard AM, Colard O. 155.  et al. 2002. TCR signal initiation machinery is pre-assembled and activated in a subset of membrane rafts. EMBO J 21:1899–908 [Google Scholar]
  156. Zech T, Ejsing CS, Gaus K, de Wet B, Shevchenko A. 156.  et al. 2009. Accumulation of raft lipids in T-cell plasma membrane domains engaged in TCR signalling. EMBO J 28:466–76 [Google Scholar]
  157. Gaus K, Chklovskaia, E, Fazekas de St, Groth B, Jessup W, Harder T. 157.  2005. Condensation of the plasma membrane at the site of T lymphocyte activation. J. Cell Biol. 171:121–31 [Google Scholar]
  158. Glebov OO, Nichols BJ. 158.  2004. Lipid raft proteins have a random distribution during localized activation of the T-cell receptor. Nat. Cell Biol. 6:238–43 [Google Scholar]
  159. Lingwood D, Simons K. 159.  2010. Lipid rafts as a membrane-organizing principle. Science 327:46–50 [Google Scholar]
  160. Nika K, Soldani C, Salek M, Paster W, Gray A. 160.  et al. 2010. Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity 32:766–77 [Google Scholar]
  161. Hui E, Vale RD. 161.  2014. In vitro membrane reconstitution of the T-cell receptor proximal signaling network. Nat. Struct. Mol. Biol. 21:133–42 [Google Scholar]
  162. James JR, Vale RD. 162.  2012. Biophysical mechanism of T-cell receptor triggering in a reconstituted system. Nature 487:64–69 [Google Scholar]
  163. Su X, Ditlev JA, Hui E, Xing W, Banjade S. 163.  et al. 2016. Phase separation of signaling molecules promotes T cell receptor signal transduction. Science 352:595–99 [Google Scholar]
  164. Taylor MJ, Husain K, Gartner ZJ, Mayor S, Vale RD. 164.  2017. A DNA-based T cell receptor reveals a role for receptor clustering in ligand discrimination. Cell 169:108–19.e20 [Google Scholar]
  165. Brocker T, Karjalainen K. 165.  1995. Signals through T cell receptor-ζ chain alone are insufficient to prime resting T lymphocytes. J. Exp. Med. 181:1653–59 [Google Scholar]
  166. Lowin-Kropf B, Shapiro VS, Weiss A. 166.  1998. Cytoskeletal polarization of T cells is regulated by an immunoreceptor tyrosine-based activation motif-dependent mechanism. J. Cell Biol. 140:861–71 [Google Scholar]
  167. Altan-Bonnet G, Germain RN. 167.  2005. Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLOS Biol 3:e356 [Google Scholar]
  168. Xie J, Huppa JB, Newell EW, Huang J, Ebert PJ. 168.  et al. 2012. Photocrosslinkable pMHC monomers stain T cells specifically and cause ligand-bound TCRs to be ‘preferentially’ transported to the cSMAC. Nat. Immunol. 13:674–80 [Google Scholar]
  169. Huang J, Brameshuber M, Zeng X, Xie J, Li QJ. 169.  et al. 2013. A single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4+ T cells. Immunity 39:846–57 [Google Scholar]
  170. Huppa JB, Ploegh HL. 170.  1997. The α chain of the T cell antigen receptor is degraded in the cytosol. Immunity 7:113–22 [Google Scholar]
  171. Yang M, Omura S, Bonifacino JS, Weissman AM. 171.  1998. Novel aspects of degradation of T cell receptor subunits from the endoplasmic reticulum (ER) in T cells: importance of oligosaccharide processing, ubiquitination, and proteasome-dependent removal from ER membranes. J. Exp. Med. 187:835–46 [Google Scholar]
  172. Yu H, Kopito RR. 172.  1999. The role of multiubiquitination in dislocation and degradation of the alpha subunit of the T cell antigen receptor. J. Biol. Chem. 274:36852–58 [Google Scholar]
  173. Ouchida R, Yamasaki S, Hikida M, Masuda K, Kawamura K. 173.  et al. 2008. A lysosomal protein negatively regulates surface T cell antigen receptor expression by promoting CD3ζ-chain degradation. Immunity 29:33–43 [Google Scholar]
  174. von Essen M, Bonefeld CM, Siersma V, Rasmussen AB, Lauritsen JP. 174.  et al. 2004. Constitutive and ligand-induced TCR degradation. J. Immunol. 173:384–93 [Google Scholar]
  175. Dumont C, Blanchard N, Di Bartolo V, Lezot N, Dufour E. 175.  et al. 2002. TCR/CD3 down-modulation and ζ degradation are regulated by ZAP-70. J. Immunol. 169:1705–12 [Google Scholar]
  176. Hou D, Cenciarelli C, Jensen JP, Nguyen HB, Weissman AM. 176.  1994. Activation-dependent ubiquitination of a T cell antigen receptor subunit on multiple intracellular lysines. J. Biol. Chem. 269:14244–47 [Google Scholar]
  177. Cenciarelli C, Hou D, Hsu KC, Rellahan BL, Wiest DL. 177.  et al. 1992. Activation-induced ubiquitination of the T cell antigen receptor. Science 257:795–97 [Google Scholar]
  178. Blum JS, Wearsch PA, Cresswell P. 178.  2013. Pathways of antigen processing. Annu. Rev. Immunol. 31:443–73 [Google Scholar]
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