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Signaling Chain Homooligomerization (SCHOOL) Model

  • Chapter
Multichain Immune Recognition Receptor Signaling

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 640))

Abstract

Multichain immune recognition receptors (MIRRs) represent a family of surface receptors expressed on different cells of the hematopoietic system and function to transduce signals leading to a variety of biologic responses. The most intriguing and distinct structural feature of MIRR family members is that extracellular recognition domains and intracellular signaling domains are located on separate subunits. The biochemical cascades triggered by MIRRs are understood in significant detail, however, the mechanism by which extracellular ligand binding initiates intracellular signal transduction processes is not clear and no model fully explains how MIRR signaling commences.

In this Chapter, I describe a novel mechanistic model of MIRR-mediated signal transduction, the signaling chain homooligomerization (SCHOOL) model. The basic concept of this model assumes that the structural similarity of the MIRRs provides the basis for the similarity in the mechanisms of MIRR-mediated transmembrane signaling. Within the SCHOOL model, MIRR triggering is considered to be a result of the ligand-induced interplay between (1) intrareceptor transmembrane interactions between MIRR recognition and signaling subunits that stabilize and maintain receptor integrity and (2) interreceptor homointeractions between MIRR signaling subunits that lead to the formation of oligomeric signaling structures, thus triggering the receptors and initiating the signaling cascade. Thus, the SCHOOL model is based on specific protein-protein interactions—biochemical processes that can be influenced and controlled. In this context, this plausible and easily testable model is fundamentally different from those previously suggested for particular MIRRs and has several important advantages. The basic principles of transmembrane signaling learned from the SCHOOL model may be used in different fields of immunology and cell biology to describe, explain and predict immunological phenomena and processes mediated by structurally related but functionally different membrane receptors. Important applications of the SCHOOL model in clinical immunology, molecular pharmacology and virology are described in the Chapters 20 and 22 of this book.

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References

  1. Keegan AD, Paul WE. Multichain immune recognition receptors: Similarities in structure and signaling pathways. Immunol Today 1992; 13:63–68.

    PubMed  CAS  Google Scholar 

  2. Sigalov AB. Immune cell signaling: A novel mechanistic model reveals new therapeutic targets. Trends Pharmacol Sci 2006; 27:518–524.

    PubMed  CAS  Google Scholar 

  3. Krogsgaard M, Davis MM. How T-cells’ see’ antigen. Nat Immunol 2005; 6:239–245.

    PubMed  CAS  Google Scholar 

  4. DeFranco AL. B-cell activation 2000. Immunol Rev 2000; 176:50–9.

    Google Scholar 

  5. Dal Porto JM, Gauld SB, Merrell KT et al. B-cell antigen receptor signaling 101. Mol Immunol 2004; 41:599–613.

    Google Scholar 

  6. Takai T. Fc receptors and their role in immune regulation and autoimmunity. J Clin Immunol 2005; 25:1–18.

    PubMed  CAS  Google Scholar 

  7. Takai T. Fc receptors: Their diverse functions in immunity and immune disorders. Springer Semin Immunopathol 2006; 28:303–304.

    PubMed  Google Scholar 

  8. Colonna M, Nakajima H, Navarro F et al. A novel family of Ig-like receptors for HLA class I molecules that modulate function of lymphoid and myeloid cells. J Leukoc Biol 1999; 66:375–381.

    PubMed  CAS  Google Scholar 

  9. Borrego F, Kabat J, Kim DK et al. Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells. Mol Immunol 2002; 38:637–660.

    PubMed  CAS  Google Scholar 

  10. Moroi M, Jung SM. Platelet glycoprotein VI: Its structure and function. Thromb Res 2004; 114:221–233.

    PubMed  CAS  Google Scholar 

  11. Barclay AN, Brown MH. The SIRP family of receptors and immune regulation. Nat Rev Immunol 2006; 6:457–464.

    PubMed  CAS  Google Scholar 

  12. Kanazawa N, Tashiro K, Miyachi Y. Signaling and immune regulatory role of the dendritic cell immunoreceptor (DCIR) family lectins: DCIR, DCAR, deain-2 and BDCA-2. Immunobiology 2004; 209:179–190.

    PubMed  CAS  Google Scholar 

  13. Biassoni R, Cantoni C, Falco M et al. Human natural killer cell activating receptors. Mol Immimol 2000; 37:1015–1024.

    CAS  Google Scholar 

  14. Biassoni R, Cantoni C, Marras D et al. Human natural killer cell receptors: Insights into their molecular function and structure. J Cell Mol Med 2003; 7:376–387.

    PubMed  CAS  Google Scholar 

  15. Aoki N, Kimura S, Xing Z. Role of DAP12 in innate and adaptive immune responses. Curr Pharm Des 2003; 9:7–10.

    PubMed  CAS  Google Scholar 

  16. Bakker AB, Baker E, Sutherland GR et al. Myeloid DAP12-associating lectin (MDL)-1 is a cell surface receptor involved in the activation of myeloid cells. Proc Natl Acad Sci USA 1999; 96:9792–9796.

    PubMed  CAS  Google Scholar 

  17. van den Berg TK, Yoder JA, Litman GW. On the origins of adaptive immunity: Innate immune receptors join the tale. Trends Immunol 2004; 25:11–16.

    PubMed  Google Scholar 

  18. Klesney-Tait J, Turnbull IR, Colonna M. The TREM receptor family and signal integration. Nat Immunol 2006; 7:1266–1273.

    PubMed  CAS  Google Scholar 

  19. Takai T. Paired immunoglobulin-like receptors and their MHC class I recognition. Immunology 2005; 115:433–440.

    PubMed  CAS  Google Scholar 

  20. Nakahashi C, Tahara-Hanaoka S, Totsuka N et al. Dual assemblies of an activating immune receptor, MAIR-II, with ITAM-bearing adapters DAP 12 and FcRgamma chain on peritoneal macrophages. J Immunol 2007; 178:765–770.

    PubMed  CAS  Google Scholar 

  21. Fujimoto M, Takatsu H, Ohno H. CMRF-35-like molecule-5 constitutes novel paired receptors, with CMRF-35-like molecule-1, to transduce activation signal upon association with FcRgamma. Int Immunol 2006; 18:1499–1508.

    PubMed  CAS  Google Scholar 

  22. Stewart CA, Vivier E, Colonna M. Strategies of natural killer cell recognition and signaling. Curr Top Microbiol Immunol 2006; 298:1–21.

    PubMed  CAS  Google Scholar 

  23. Reth M. Antigen receptor tail clue. Nature 1989; 338:383–384.

    PubMed  CAS  Google Scholar 

  24. Songyang Z, Shoelson SE, Chaudhuri M et al. SH2 domains recognize specific phosphopeptide sequences. Cell 1993; 72:767–778.

    PubMed  CAS  Google Scholar 

  25. Wu J, Cherwinski H, Spies T et al. DAP1O and DAP12 form distinct, but functionally cooperative, receptor complexes in natural killer cells. J Exp Med 2000; 192:1059–1068.

    PubMed  CAS  Google Scholar 

  26. Manolios N, Bonifacino JS, Klausner RD. Transmembrane helical interactions and the assembly of the T-cell receptor complex. Science 1990; 249:274–277.

    PubMed  CAS  Google Scholar 

  27. Call ME, Pyrdol J, Wiedmann M et al. The organizing principle in the formation of the T-cell receptor-CD3 complex. Cell 2002; 111:967–979.

    PubMed  CAS  Google Scholar 

  28. Michnoflf CH, Parikh VS, Lelsz DL et al. Mutations within the NH2-terminal transmembrane domain of membrane immunoglobulin (Ig) M alters Ig alpha and Ig beta association and signal transduction. J Biol Chem 1994; 269:24237–24244.

    Google Scholar 

  29. Daeron M. Fc receptor biology. Annu Rev Immunol 1997; 15:203–234.

    PubMed  CAS  Google Scholar 

  30. Feng J, Garrity D, Call ME et al. Convergence on a distinctive assembly mechanism by unrelated families of activating immune receptors. Immunity 2005; 22:427–438.

    PubMed  CAS  Google Scholar 

  31. Feng J, Call ME, Wucherpfennig KW. The assembly of diverse immune receptors is focused on a polar membrane-embedded interaction site. PLoS Biol 2006; 4:el42.

    Google Scholar 

  32. Bakema JE, de Haij S, den Hartog-Jager CF et al. Signaling through mutants of the IgA receptor CD89 and consequences for Fc receptor gamma-chain interaction. J Immunol 2006; 176:3603–3610.

    PubMed  CAS  Google Scholar 

  33. Varin-Blank N, Metzger H. Surface expression of mutated subunits of the high affinity mast cell receptor for IgE. J Biol Chem 1990; 265:15685–15694.

    PubMed  CAS  Google Scholar 

  34. Stevens TL, Blum JH, Foy SP et al. A mutation of the mu transmembrane that disrupts endoplasmic reticulum retention. Effects on association with accessory proteins and signal transduction. J Immunol 1994; 152:4397–4406.

    PubMed  CAS  Google Scholar 

  35. Zidovetzki R, Rost B, Pecht I. Role of transmembrane domains in the functions of B-and T-cell receptors. Immunol Lett 1998; 64:97–107.

    PubMed  CAS  Google Scholar 

  36. Blum JH, Stevens TL, DeFranco AL. Role of the mu immunoglobulin heavy chain transmembrane and cytoplasmic domains in B-cell antigen receptor expression and signal transduction. J Biol Chem 1993; 268:27236–27245.

    PubMed  CAS  Google Scholar 

  37. Ra C, Jouvin MH, Kinet JP. Complete structure of the mouse mast cell receptor for IgE (Fc epsilon RI) and surface expression of chimeric receptors (rat-mouse-human) on transfected cells. J Biol Chem 1989; 264:15323–15327.

    PubMed  CAS  Google Scholar 

  38. Rudd CE. Disabled receptor signaling and new primary immunodeficiency disorders. N Engl J Med 2006; 354:1874–1877.

    PubMed  CAS  Google Scholar 

  39. Gomes MM, Herr AB. IgA and IgA-specific receptors in human disease: structural and functional insights into pathogenesis and therapeutic potential. Springer Semin Immunopathol 2006; 28:383–395.

    PubMed  CAS  Google Scholar 

  40. Honda Z. Fcepsilon-and Fcgamma-receptor signaling in diseases. Springer Semin Immunopathol 2006; 28:365–375.

    PubMed  CAS  Google Scholar 

  41. Moretta A, Bottino C, Vitale M et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 2001; 19:197–223.

    PubMed  CAS  Google Scholar 

  42. Clemetson KJ. Platelet receptors and their role in diseases. Clin Chem Lab Med 2003; 41:253–260.

    PubMed  CAS  Google Scholar 

  43. Ortega E. How do multichain immune recognition receptors signal? A structural hypothesis. Mol Immunol 1995; 32:941–945.

    PubMed  CAS  Google Scholar 

  44. Reth M. Oligomeric antigen receptors: A new view on signaling for the selection of lymphocytes. Trends Immunol 2001; 22:356–360.

    PubMed  CAS  Google Scholar 

  45. Langlet C, Bernard AM, Drevot P et al. Membrane rafts and signaling by the multichain immune recognition receptors. Curr Opin Immunol 2000; 12:250–255.

    PubMed  CAS  Google Scholar 

  46. Dykstra M, Cherukuri A, Pierce SK. Rafts and synapses in the spatial organization of immune cell signahng receptors. J Leukoc Biol 2001; 70:699–707.

    PubMed  CAS  Google Scholar 

  47. Sigalov A. Multi-chain immune recognition receptors: Spatial organization and signal transduction. Semin Immunol 2005; 17:51–64.

    PubMed  CAS  Google Scholar 

  48. Sigalov AB. Multichain immune recognition receptor signaling: Different players, same game? Trends Immunol 2004; 25:583–589.

    PubMed  CAS  Google Scholar 

  49. Sigalov AB. Transmembrane interactions as immunotherapeutic targets: Lessons from viral pathogenesis. Adv Exp Med Biol 2007; 601:335–344.

    PubMed  Google Scholar 

  50. Heldin CH. Dimerization of cell surface receptors in signal transduction. Cell 1995; 80:213–223.

    PubMed  CAS  Google Scholar 

  51. Metzger H. Transmembrane signaling: The joy of aggregation. J Immunol 1992; 149:1477–1487.

    PubMed  CAS  Google Scholar 

  52. Boniface JJ, Rabinowitz JD, Wulfing C et al. Initiation of signal transduction through the T-cell receptor requires the multivalent engagement of peptide/MHC ligands [corrected]. Immimity 1998; 9:459–466.

    CAS  Google Scholar 

  53. Holowka D, Baird B. Antigen-mediated IGE receptor aggregation and signaling: A window on cell surface structure and dynamics. Annu Rev Biophys Biomol Struct 1996; 25:79–112.

    PubMed  CAS  Google Scholar 

  54. Thyagarajan R, Arunkumar N, Song W. Polyvalent antigens stabilize B-cell antigen receptor surface signaling microdomains. J Immunol 2003; 170:6099–6106.

    PubMed  CAS  Google Scholar 

  55. Bankovich AJ, Raunser S, Juo ZS et al. Structural insight into preB cell receptor function. Science 2007; 316:291–294.

    PubMed  CAS  Google Scholar 

  56. Puffer EB, Pontrello JK, Hollenbeck JJ et al. Activating B-cell signaling with defined multivalent ligands. ACS Chem Biol 2007; 2:252–262.

    PubMed  CAS  Google Scholar 

  57. Deng L, Langley RJ, Brown PH et al. Structural basis for the recognition of mutant self by a tumor-specific, MHC class Il-restricted T-cell receptor. Nat Immunol 2007; 8:398–408.

    PubMed  CAS  Google Scholar 

  58. Adams EJ, Chien YH, Garcia KC. Structure of a gammadelta T-cell receptor in complex with the nonclassical MHC T22. Science 2005; 308:227–231.

    PubMed  CAS  Google Scholar 

  59. Bachmann MF, Ohashi PS. The role of T-cell receptor dimerization in T-cell activation. Immunol Today 1999; 20:568–576.

    PubMed  CAS  Google Scholar 

  60. Bachmann MF, Salzmann M, Oxenius A et al. Formation of TCR dimers/trimers as a crucial step for T-cell activation. Eur J Immunol 1998; 28:2571–2579.

    PubMed  CAS  Google Scholar 

  61. DeFranco AL, Gold MR, Jakway JP. B-lymphocyte signal transduaion in response to anti-immunoglobulin and bacterial lipopolysaccharide. Immunol Rev 1987; 95:161–176.

    PubMed  CAS  Google Scholar 

  62. Posner RG, Savage PB, Peters AS et al. A quantitative approach for studying IgE-FcepsilonRI aggregation. Mol Immunol 2002; 38:1221–1228.

    PubMed  CAS  Google Scholar 

  63. Draberova L, Lebduska P, Halova I et al. Signaling assemblies formed in mast cells activated via Fcepsilon receptor I dimers. Eur J Immunol 2004; 34:2209–2219.

    PubMed  CAS  Google Scholar 

  64. Horii K, Kahn ML, Herr AB. Structural basis for platelet collagen responses by the immune-type receptor glycoprotein VI. Blood 2006; 108:936–942.

    PubMed  CAS  Google Scholar 

  65. Cochran JR, Cameron TO, Stern LJ. The relationship of MHC-peptide binding and T-cell activation probed using chemically defined MHC class II oligomers. Inmiunity 2000; 12:241–250.

    CAS  Google Scholar 

  66. Fahmy TM, Bieler JG, Schneck JP. Probing T-cell membrane organization using dimeric MHC-Ig complexes. J Immunol Methods 2002; 268:93–106.

    PubMed  CAS  Google Scholar 

  67. Kiessling LL, Gestwicki JE, Strong LE. Synthetic multivalent ligands as probes of signal transduction. Angew Chem Int Ed Engl 2006; 45:2348–2368.

    PubMed  CAS  Google Scholar 

  68. Klemm JD, Schreiber SL, Crabtree GR. Dimerization as a regulatory mechanism in signal transduction. Annu Rev Immunol 1998; 16:569–592.

    PubMed  CAS  Google Scholar 

  69. Garrity D, Call ME, Feng J et al. The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure. Proc Natl Acad Sci USA 2005; 102:7641–7646.

    PubMed  CAS  Google Scholar 

  70. Radaev S, Kattah M, Rostro B et al. Crystal structure of the human myeloid cell activating receptor TREM-1. Structure 2003; 11:1527–1535.

    PubMed  CAS  Google Scholar 

  71. Berlanga O, Bor-Sanz T, James JR et al. Glycoprotein VI oligomerization in cell lines and platelets. J Thromb Haemost 2007; 5:1026–1033.

    PubMed  CAS  Google Scholar 

  72. Symer DE, Dintzis RZ, Diamond DJ et al. Inhibition or activation of human T-cell receptor transfectants is controlled by defined, soluble antigen arrays. J Exp Med 1992; 176:1421–1430.

    PubMed  CAS  Google Scholar 

  73. Schweitzer-Stenner R, Tamir I, Pecht I. Analysis of Fc(epsilon)RI-mediated mast cell stimulation by surface-carried antigens. Biophys J 1997; 72:2470–2478.

    PubMed  CAS  Google Scholar 

  74. Patrick SM, Kim S, Braunstein NS et al. Dependence of T-cell activation on area of contact and density of a ligand-coated surface. J Immunol Methods 2000; 241:97–108.

    PubMed  CAS  Google Scholar 

  75. Germain RN. T-cell signaling: the importance of receptor clustering. Curr Biol 1997; 7:R640–644.

    PubMed  CAS  Google Scholar 

  76. Alam SM, Davies GM, Lin CM et al. Qualitative and quantitative differences in T-cell receptor binding of agonist and antagonist ligands. Immunity 1999; 10:227–237.

    PubMed  CAS  Google Scholar 

  77. Pribluda VS, Pribluda C, Metzger H. Transphosphorylation as the mechanism by which the high-affinity receptor for IgE is phosphorylated upon aggregation. Proc Natl Acad Sci USA 1994; 91:11246–11250.

    PubMed  CAS  Google Scholar 

  78. Sigalov A, Aivazian D, Stern L. Homooligomerization of the cytoplasmic domain of the T-cell receptor zeta chain and of other proteins containing the immunoreceptor tyrosine-based activation motif. Biochemistry 2004; 43:2049–2061.

    PubMed  CAS  Google Scholar 

  79. Berko D, Carmi Y, Cafri G et al. Membrane-anchored beta 2-microglobulin stabilizes a highly receptive state of MHC class I molecules. J Immunol 2005; 174:2116–2123.

    PubMed  CAS  Google Scholar 

  80. Talbott M, Hare M, Nyarko A et al. Folding is coupled to dimerization of Tctex-1 dynein light chain. Biochemistry 2006; 45:6793–6800.

    PubMed  CAS  Google Scholar 

  81. Sigalov AB, Zhuravleva AV, Orekhov VY. Binding of intrinsically disordered proteins is not necessarily accompanied by a structural transition to a folded form. Biochimie 2007; 89:419–421.

    PubMed  CAS  Google Scholar 

  82. Sigalov AB, Aivazian DA, Uversky VN et al. Lipid-binding activity of intrinsically unstructured cytoplasmic domains of multichain immune recognition receptor signaling subunits. Biochemistry 2006; 45:15731–15739.

    PubMed  CAS  Google Scholar 

  83. Pitcher LA, van Oers NS. T-cell receptor signal transmission: Who gives an ITAM? Trends Immunol 2003; 24:554–560.

    PubMed  CAS  Google Scholar 

  84. Pike KA, Baig E, Ratcliffe MJ. The avian B-cell receptor complex: Distinct roles of Igalpha and Igbeta in B-cell development. Immunol Rev 2004; 197:10–25.

    PubMed  CAS  Google Scholar 

  85. Storch B, Meixlsperger S, Jumaa H. The Ig-alpha ITAM is required for efficient differentiation but not proliferation of preB cells. Eur J Immunol 2007; 37:252–260.

    PubMed  CAS  Google Scholar 

  86. Gazumyan A, Reichlin A, Nussenzweig MC. Ig beta tyrosine residues contribute to the control of B-cell receptor signaling by regulating receptor internalization. J Exp Med 2006; 203:1785–1794.

    PubMed  CAS  Google Scholar 

  87. Lin S, Cicala C, Scharenberg AM et al. The Fc(epsilon)RIbeta subunit functions as an amplifier of Fc(epsilon)RIgamma-mediated cell activation signals. Cell 1996; 85:985–995.

    PubMed  CAS  Google Scholar 

  88. Sanchez-Mejorada G, Rosales C. Signal transduction by immunoglobulin Fc receptors. J Leukoc Biol 1998; 63:521–533.

    PubMed  CAS  Google Scholar 

  89. Lysechko TL, Ostergaard HL. Differential Src family kinase activity requirements for CD3 zeta phosphorylation/ ZAP70 recruitment and CD3 epsilon phosphorylation. J Immunol 2005; 174:7807–7814.

    PubMed  CAS  Google Scholar 

  90. Kuhns MS, Davis MM. Disruption of extracellular interactions impairs T-cell receptor-CD3 complex stability and signaling. Immunity 2007; 26:357–369.

    PubMed  CAS  Google Scholar 

  91. Chau LA, Bluestone JA, Madrenas J. Dissociation of intracellular signaling pathways in response to partial agonist ligands of the T-cell receptor. J Exp Med 1998; 187:1699–1709.

    PubMed  CAS  Google Scholar 

  92. Jensen WA, Pleiman CM, Beaufils P et al. Qualitatively distinct signaling through T-cell antigen receptor subunits. Eur J Immunol 1997; 27:707–716.

    PubMed  CAS  Google Scholar 

  93. Pitcher LA, Mathis MA, Young JA et al. The CD3 gammaepsilon/deltaepsilon signaling module provides normal T-cell functions in the absence of the TCR zeta immunoreceptor tyrosine-based activation motifs. Eur J Immunol 2005; 35:3643–3654.

    PubMed  CAS  Google Scholar 

  94. Kesti T, Ruppelt A, Wang JH et al. Reciprocal Regulation of SH3 and SH2 Domain Binding via Tyrosine Phosphorylation of a Common Site in CD3 epsilon. J Immunol 2007; 179:878–885.

    PubMed  CAS  Google Scholar 

  95. Chae WJ, Lee HK, Han JH et al. Qualitatively differential regulation of T-cell activation and apoptosis by T-cell receptor zeta chain ITAMs and their tyrosine residues. Int Immunol 2004; 16:1225–1236.

    PubMed  CAS  Google Scholar 

  96. Wines BD, Trist HM, Monteiro RC et al. Fc receptor gamma chain residues at the interface of the cytoplasmic and transmembrane domains affect association with FcalphaRI, surface expression and flmction. J Biol Chem 2004; 279:26339–26345.

    PubMed  CAS  Google Scholar 

  97. Kikuchi-Maki A, Catina TL, Campbell KS. Cutting edge: KIR2DL4 transduces signals into human NK cells through association with the Fc receptor gamma protein. J Immunol 2005; 174:3859–3863.

    PubMed  CAS  Google Scholar 

  98. DeFranco AL, Mittelstadt PR, Blum JH et al. Mechanism of B-cell antigen receptor function: transmembrane signaling and triggering of apoptosis. Adv Exp Med Biol 1994; 365:9–22.

    PubMed  CAS  Google Scholar 

  99. Morton HC, van den Heri-Oudijk IE, Vossebeld P et al. Functional association between the human myeloid immunoglobulin A Fc receptor (CD89) and FcR gamma chain. Molecular basis for CD89/FcR gamma chain association. J Biol Chem 1995; 270:29781–29787.

    PubMed  CAS  Google Scholar 

  100. Kim MK, Huang ZY, Hwang PH et al. Fcgamma receptor transmembrane domains: role in cell surface expression, gamma chain interaction and phagocytosis. Blood 2003; 101:4479–4484.

    PubMed  CAS  Google Scholar 

  101. Arkin M. Protein-protein interactions and cancer: Small molecules going in for the kill. Curr Opin Chem Biol 2005; 9:317–324.

    PubMed  CAS  Google Scholar 

  102. Fry DC. Protein-protein interactions as targets for small molecule drug discovery. Biopolymers 2006; 84:535–552.

    PubMed  CAS  Google Scholar 

  103. Loregian A, Palu G. Disruption of protein-protein interactions: Towards new targets for chemotherapy. J Cell Physiol 2005; 204:750–762.

    PubMed  CAS  Google Scholar 

  104. Angelov GS, Guillaimie P, Cebecauer M et al. Soluble MHC-peptide complexes containing long rigid linkers abolish CTL-mediated cytotoxicity. J Immunol 2006; 176:3356–3365.

    PubMed  CAS  Google Scholar 

  105. Rotzschke O, Falk K, Strominger JL. Superactivation of an immune response triggered by oligomerized T-cell epitopes. Proc Natl Acad Sci USA 1997; 94:14642–14647.

    PubMed  CAS  Google Scholar 

  106. Tamir I, Schweitzer-Stenner R, Pecht I. Immobilization of the type I receptor for IgE initiates signal transduction in mast cells. Biochemistry 1996; 35:6872–6883.

    PubMed  CAS  Google Scholar 

  107. Yang H, Parkhouse RM. Differential activation requirements associated with stimulation of T-cells via different epitopes of CD3. Immunology 1998; 93:26–32.

    PubMed  CAS  Google Scholar 

  108. Niederberger N, Buehler LK, Ampudia J et al. Thymocyte stimulation by anti-TCR-beta, but not by anti-TCR-alpha, leads to induction of developmental transcription program. J Leukoc Biol 2005; 77:830–841.

    PubMed  CAS  Google Scholar 

  109. Carreno LJ, Gonzalez PA, Kalergis AM. Modulation of T-cell function by TCR/pMHC binding kinetics. Immunobiology 2006; 211:47–64.

    PubMed  CAS  Google Scholar 

  110. Holler PD, Lim AR, Cho BK et al. CD8(-) T-cell transfectants that express a high affinity T-cell receptor exhibit enhanced peptide-dependent activation. J Exp Med 2001; 194:1043–1052.

    PubMed  CAS  Google Scholar 

  111. Ortega E, Schweitzer-Stenner R, Pecht I. Possible orientational constraints determine secretory signals induced by aggregation of IgE receptors on mast cells. EMBO J 1988; 7:4101–4109.

    PubMed  CAS  Google Scholar 

  112. Pecht I, Ortega E, Jovin TM. Rotational dynamics of the Fc epsilon receptor on mast cells monitored by specific monoclonal antibodies and IgE. Biochemistry 1991; 30:3450–3458.

    PubMed  CAS  Google Scholar 

  113. Gil D, Schamel WW, Montoya M et al. Recruitment of Nek by CD3 epsilon reveals a ligand-induced conformational change essential for T-cell receptor signaling and synapse formation. Cell 2002; 109:901–912.

    PubMed  CAS  Google Scholar 

  114. Tamir I, Cambier JC. Antigen receptor signaling: Integration of protein tyrosine kinase functions.Oncogene 1998; 17:1353–1364.

    PubMed  CAS  Google Scholar 

  115. Sulzer B, Perelson AS. Immunons revisited: Binding of multivalent antigens to B-cells. Mol Immunol 1997; 34:63–74.

    PubMed  CAS  Google Scholar 

  116. Reth M, Wienands J. Initiation and processing of signals from the B-cell antigen receptor. Annu Rev Immunol 1997; 15:453–479.

    PubMed  CAS  Google Scholar 

  117. Nimmerjahn F. Activating and inhibitory FcgammaRs in autoimmune disorders. Springer Semin Immunopathol 2006; 28:305–319.

    PubMed  CAS  Google Scholar 

  118. Maurer D, Fiebiger E, Reininger B et al. Fc epsilon receptor I on dendritic cells delivers IgE-bound multivalent antigens into a cathepsin S-dependent pathway of MHC class II presentation. J Immunol 1998; 161:2731–2739.

    PubMed  CAS  Google Scholar 

  119. Lara M, Ortega E, Pecht I et al. Overcoming the signaling defect of Lyn-sequestering, signal-curtailing FcepsilonRI dimers: Aggregated dimers can dissociate from Lyn and form signaling complexes with Syk.J Immunol 2001; 167:4329–4337.

    PubMed  CAS  Google Scholar 

  120. Metzger H. The high affinity receptor for IgE, FcepsilonRI. Novartis Found Symp 2004; 257:51–59; discussion 59–64, 98–100, 276–185.

    PubMed  CAS  Google Scholar 

  121. Metzger H, Eglite S, Haleem-Smith H et al. Quantitative aspects of signal transduction by the receptor with high affinity for IgE. Mol Immunol 2002; 38:1207–1211.

    PubMed  CAS  Google Scholar 

  122. Holowka D, Sil D, Torigoe C et al. Insights into immunoglobulin E receptor signaling from structurally defined ligands. Immunol Rev 2007; 217:269–279.

    PubMed  CAS  Google Scholar 

  123. Radaev S, Sun PD. Structure and function of natural killer cell surface receptors. Annu Rev Biophys Biomol Struct 2003; 32:93–114.

    PubMed  CAS  Google Scholar 

  124. Natarajan K, Dimasi N, Wang J et al. Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. Annu Rev Immunol 2002; 20:853–885.

    PubMed  CAS  Google Scholar 

  125. Turnbuu IR, Colonna M. Activating and inhibitory functions of DAP12. Nat Rev Immunol 2007; 7:155–161.

    Google Scholar 

  126. Posner RG, Paar JM, Licht A et al. Interaction of a monoclonal IgE-specific antibody with cell-surface IgE-Fc epsilon RI: characterization of equilibrium binding and secretory response. Biochemistry 2004; 43:11352–11360.

    PubMed  CAS  Google Scholar 

  127. Schweitzer-Stenner R, Ortega E, Pecht I. Kinetics of Fc epsilon RI dimer formation by specific monoclonal antibodies on mast cells. Biochemistry 1994; 33:8813–8825.

    PubMed  CAS  Google Scholar 

  128. Kent UM, Mao SY, Wbfsy C et al. Dynamics of signal transduction after aggregation of cell-surface receptors: studies on the type I receptor for IgE. Proc Natl Acad Sci USA 1994; 91:3087–3091.

    PubMed  CAS  Google Scholar 

  129. Yamasaki S, Ishikawa E, Kohno M et al. The quantity and duration of FcRgamma signals determine mast cell degranulation and survival. Blood 2004; 103:3093–3101.

    PubMed  CAS  Google Scholar 

  130. Gibbs BF, Rathling A, Zillikens D et al. Initial Fc epsilon Rl-mediated signal strength plays a key role in regulating basophil signaling and deactivation. J Allergy Clin Immunol 2006; 118:1060–1067.

    PubMed  CAS  Google Scholar 

  131. Torigoe C, Inman JK, Metzger H. An unusual mechanism for ligand antagonism. Science 1998; 281:568–572.

    PubMed  CAS  Google Scholar 

  132. Pasquier B, Launay P, Kanamaru Y et al. Identification of F calphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. Immunity 2005; 22:31–42.

    PubMed  CAS  Google Scholar 

  133. Miura Y, Takahashi T, Jung SM et al. Analysis of the interaction of platelet collagen receptor glycoprotein VI (GPVI) with collagen. A dimcric form of GPVI, but not the monomeric form, shows affinity to fibrous collagen. J Biol Chem 2002; 277:46197–46204.

    PubMed  CAS  Google Scholar 

  134. Varma R, Campi G, Yokosuka T et al. T-cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 2006; 25:117–127.

    PubMed  CAS  Google Scholar 

  135. Jiang G, Hunter T. Receptor signaling: when dimerization is not enough. Curr Biol 1999; 9:R568–571.

    PubMed  CAS  Google Scholar 

  136. Livnah O, Johnson DL, Stura EA et al. An antagonist peptide-EPO receptor complex suggests that receptor dimerization is not sufficient for activation. Nat Struct Biol 1998; 5:993–1004.

    PubMed  CAS  Google Scholar 

  137. Syed RS, Reid SW, Li C et al. Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature 1998; 395:511–516.

    PubMed  CAS  Google Scholar 

  138. Greiser JS, Stross C, Heinrich PC et al. Orientational constraints of the gpl30 intracellular juxtamembrane domain for signaling. J Biol Chem 2002; 277:26959–26965.

    PubMed  CAS  Google Scholar 

  139. Gay NJ, Gangloff M, Weber AN. Toll-like receptors as molecular switches. Nat Rev Immunol 2006; 6:693–698.

    PubMed  CAS  Google Scholar 

  140. Mescher MF, Agarwal P, Casey KA et al. Molecular basis for checkpoints in the CD8 T-cell response: Tolerance versus activation. Semin Immunol 2007; 19:153–161.

    PubMed  CAS  Google Scholar 

  141. Colombetti S, Benigni F, Basso V et al. Clonal anergy is maintained independently of T-cell proliferation. J Immunol 2002; 169:6178–6186.

    PubMed  CAS  Google Scholar 

  142. Choi S, Schwartz RH. Molecular mechanisms for adaptive tolerance and other T-cell anergy models. Semin Immunol 2007; 19:140–152.

    PubMed  CAS  Google Scholar 

  143. Chiodetti L, Choi S, Barber DL et al. Adaptive tolerance and clonal anergy are distinct biochemical states. J Immunol 2006; 176:2279–2291.

    PubMed  CAS  Google Scholar 

  144. Recio MJ, Moreno-Pelayo MA, Kilic SS et al. Diffisrential biological role of CD3 chains revealed by human immunodeficiencies. J Immunol 2007; 178:2556–2564.

    PubMed  CAS  Google Scholar 

  145. Gil D, Schrum AG, Alarcon B et al. T-cell receptor engagement by peptide-MHC ligands induces a conformational change in the CD3 complex of thymocytes. J Exp Med 2005; 201:517–522.

    PubMed  CAS  Google Scholar 

  146. Risueno RM, Gil D, Fernandez E et al. Ligand-induced conformational change in the T-cell receptor associated with productive immune synapses. Blood 2005; 106:601–608.

    PubMed  CAS  Google Scholar 

  147. Risueno RM, van Santen HM, Alarcon B. A conformational change senses the strength of T-cell receptor-ligand interaction during thymic selection. Proc Natl Acad Sci USA 2006; 103:9625–9630.

    PubMed  CAS  Google Scholar 

  148. Vilen BJ, Nakamura T, Cambier JC. Antigen-stimidated dissociation of BCR mIg from Ig-alpha/Ig-beta: implications for receptor desensitization. Immunity 1999; 10:239–248.

    PubMed  CAS  Google Scholar 

  149. Vilen BJ, FamigUetti SJ, Carbone AM et al. B-cell antigen receptor desensitization: Disruption of receptor coupling to tyrosine kinase activation. J Immunol 1997; 159:231–243.

    PubMed  CAS  Google Scholar 

  150. Cambier JC, Fisher CL, Pickles H et al. Dual molecular mechanisms mediate ligand-induced membrane Ig desensitization. J Immunol 1990; 145:13–19.

    PubMed  CAS  Google Scholar 

  151. Vilen BJ, Burke KM, Skater M et al. Transmodulation of BCR signaling by transduction-incompetent antigen receptors: Implications for impaired signaling in anergic B-cells. J Immunol 2002; 168:4344–4351.

    PubMed  CAS  Google Scholar 

  152. Arnon TI, Achdout H, Levi O et al. Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat Immunol 2005; 6:515–523.

    PubMed  CAS  Google Scholar 

  153. Levit MN, Liu Y, Stock JB. Stimulus response coupling in bacterial chemotaxis: Receptor dimers in signalling arrays. Mol Microbiol 1998; 30:459–466.

    PubMed  CAS  Google Scholar 

  154. Sourjik V, Berg HC. Functional interactions between receptors in bacterial chemotaxis. Nature 2004; 428:437–441.

    PubMed  CAS  Google Scholar 

  155. Sourjik V. Receptor clustering and signal processing in E. coli chemotaxis. Trends Microbiol 2004; 12:569–576.

    PubMed  CAS  Google Scholar 

  156. Kawaguchi M, Eckels DD. Differential activation through the TCR-CD3 complex affects the requirement for costimulation of human T-cells. Hum Immunol 1995; 43:136–148.

    PubMed  CAS  Google Scholar 

  157. Lanier LL, Ruitenberg JJ, Allison JP et al. Distinct epitopes on the T-cell antigen receptor of HPB-ALL tumor cells identified by monoclonal antibodies. J Immunol 1986; 137:2286–2292.

    PubMed  CAS  Google Scholar 

  158. Schlitt HJ, Kurrle R, Wonigeit K. T-cell activation by monoclonal antibodies directed to different epitopes on the human T-cell receptor/CD3 complex: Evidence for two different modes of activation. Eur J Immunol 1989; 19:1649–1655.

    PubMed  CAS  Google Scholar 

  159. Schwinzer R, Franklin RA, Domenico J et al. Monoclonal antibodies directed to different epitopes in the CD3-TCR complex induce different states of competence in resting human T-cells. J Immunol 1992; 148:1322–1328.

    PubMed  CAS  Google Scholar 

  160. Yoon ST, Dianzani U, Bottomly K et al. Both high and low avidity antibodies to the T-cell receptor can have agonist or antagonist activity. Immunity 1994; 1:563–569.

    PubMed  CAS  Google Scholar 

  161. Reich Z, Boniface JJ, Lyons DS et al. Ligand-specific oligomerization of T-cell receptor molecules. Nature 1997; 387:617–620.

    PubMed  CAS  Google Scholar 

  162. Garboczi DN, Ghosh P, Utz U et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 1996; 384:134–141.

    PubMed  CAS  Google Scholar 

  163. Abastado JP, Lone YC, Casrouge A et al. Dimerization of soluble major histocompatibility complex-peptide complexes is sufficient for activation of T-cell hybridoma and induction of unresponsiveness. J Exp Med 1995; 182:439–447.

    PubMed  CAS  Google Scholar 

  164. Lindstedt R, Monk N, Lombardi G et al. Amino acid substitutions in the putative MHC class II “dimer of dimers” interface inhibit CD4+ T-cell activation. J Immunol 2001; 166:800–808.

    PubMed  CAS  Google Scholar 

  165. Hayball JD, Lake RA. The immune function of MHC class II molecules mutated in the putative superdimer interface. Mol Cell Biochem 2005; 273:1–9.

    PubMed  CAS  Google Scholar 

  166. Watts TH. T-cell activation by preformed, long-lived Ia-peptide complexes. Quantitative aspects. J Immunol 1988; 141:3708–3714.

    PubMed  CAS  Google Scholar 

  167. Rubin B, Knibiehler M, Gairin JE. Allosteric Changes in the TCR/CD3 Structure Upon Interaction With Extra-or Intra-cellular Ligands. Scand J Immunol 2007; 66:228–237.

    PubMed  CAS  Google Scholar 

  168. Cochran JR, Cameron TO, Stone JD et al. Receptor proximity, not intermolecular orientation, is critical for triggering T-cell activation. J Biol Chem 2001; 276:28068–28074.

    PubMed  CAS  Google Scholar 

  169. Cebecauer M, Guillaume P, Hozak P et al. Soluble MHC-peptide complexes induce rapid death of CD8+ CTL. J Immunol 2005; 174:6809–6819.

    PubMed  CAS  Google Scholar 

  170. Yamasaki S, Ishikawa E, Sakuma M et al. Mechanistic basis of pre-T-cell receptor-mediated autonomous signaling critical for thymocyte development. Nat Immunol 2006; 7:67–75.

    PubMed  CAS  Google Scholar 

  171. Yamasaki S, Saito T. Molecular basis for preTCR-mediated autonomous signaling. Trends Immunol 2007; 28:39–43.

    PubMed  CAS  Google Scholar 

  172. Geisberger R, Crameri R, Achatz G. Models of signal transduction through the B-cell antigen receptor. Immunology 2003; 110:401–410.

    PubMed  CAS  Google Scholar 

  173. Yamashita T, Mao SY, Metzger H. Aggregation of the high-affinity IgE receptor and enhanced activity of p53/561yn protein-tyrosine kinase. Proc Natl Acad Sci USA 1994; 91:11251–11255.

    PubMed  CAS  Google Scholar 

  174. Kane P, Erickson J, Fewtrell C et al. Cross-linking of IgE-receptor complexes at the cell surface: Synthesis and characterization of a long bivalent hapten that is capable of triggering mast cells and rat basophilic leukemia cells. Mol Immunol 1986; 23:783–790.

    PubMed  CAS  Google Scholar 

  175. Kanamam Y, Blank U, Monteiro RC. IgA Fc receptor I is a molecular switch that determines IgA activating or inhibitory functions. Contrib Nephrol 2007; 157:148–152.

    Google Scholar 

  176. Li P, Morris DL, Willcox BE et al. Complex structure of the activating immunoreceptor NKG2D and its MHC class I-likc ligand MICA. Nat Immunol 2001; 2:443–451.

    PubMed  CAS  Google Scholar 

  177. Strong RK. Asymmetric ligand recognition by the activating natural killer cell receptor NKG2D, a symmetric homodimer. Mol Immunol 2002; 38:1029–1037.

    PubMed  CAS  Google Scholar 

  178. Farndale RW. Collagen-induced platelet activation. Blood Cells Mol Dis 2006; 36:162–165.

    PubMed  CAS  Google Scholar 

  179. Smethurst PA, Onley DJ, Jarvis GE et al. Structural basis for the platelet-collagen interaction: The smallest motif within collagen that recognizes and activates platelet Glycoprotein VI contains two glycine-proline-hydroxyproline triplets. J Biol Chem 2007; 282:1296–1304.

    PubMed  CAS  Google Scholar 

  180. Lu Q, Navdaev A, Clemetson JM et al. Snake venom C-type lectins interacting with platelet receptors. Structure-function relationships and effects on haemostasis. Toxicon 2005; 45:1089–1098.

    PubMed  CAS  Google Scholar 

  181. Kato K, Furihata K, Cheli Y et al. Effect of multimer size and a natural dimorphism on the binding of convulxin to platelet glycoprotein (GP)VI. J Thromb Haemost 2006; 4:1107–1113.

    PubMed  CAS  Google Scholar 

  182. Singer KL, Mostov KE. Dimerization of the polymeric immunoglobulin receptor controls its transcytotic trafficking. Mol Biol Cell 1998; 9:901–915.

    PubMed  CAS  Google Scholar 

  183. Mocsai A, Abram CL, Jakus Z et al. Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat Immunol 2006; 7:1326–1333.

    PubMed  CAS  Google Scholar 

  184. Li R, Mitra N, Gratkowski H et al. Activation of integrin alphaIIbbeta3 by modulation of transmembrane helix associations. Science 2003; 300:795–798.

    PubMed  CAS  Google Scholar 

  185. Hantgan RR, Lyles DS, Mallett TC et al. Ligand binding promotes the entropy-driven oligomerization of integrin alpha IIb beta 3. J Biol Chem 2003; 278:3417–3426.

    PubMed  CAS  Google Scholar 

  186. Schamel WW, Arechaga I, Risueno RM et al. Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response. J Exp Med 2005; 202:493–503.

    PubMed  CAS  Google Scholar 

  187. Iber D, Gruhn T. Organisation of B-cell receptors on the cell membrane. Syst Biol (Stevenage) 2006; 153:401–404.

    CAS  Google Scholar 

  188. Matsuuchi L, Gold MR. New views of BCR structure and organization. Curr Opin Immunol 2001; 13:270–277.

    PubMed  CAS  Google Scholar 

  189. Schamel WW, Reth M. Monomeric and oligomeric complexes of the B-cell antigen receptor.Immunity 2000; 13:5–14.

    PubMed  CAS  Google Scholar 

  190. Moss WC, Irvine DJ, Davis MM et al. Quantifying signaling-induced reorientation of T-cell receptors during immunological synapse formation. Proc Natl Acad Sci USA 2002; 99:15024–15029.

    PubMed  CAS  Google Scholar 

  191. Minguet S, Swamy M, Alarcon B et al. Full activation of the T-cell receptor requires both clustering and conformational changes at CD3. Immunity 2007; 26:43–54.

    PubMed  CAS  Google Scholar 

  192. Ding YH, Baker BM, Garboczi DN et al. Four A6-TCR/peptide/HLA-A2 structures that generate very different T-cell signals are nearly identical. Immunity 1999; 11:45–56.

    PubMed  CAS  Google Scholar 

  193. Ortega E, Lara M, Lee I et al. Lyn dissociation from phosphorylated Fc epsilon RI subunits: A new regulatory step in the Fc epsilon RI signaling cascade revealed by studies of Fc epsilon RI dimer signaling activity. J Immunol 1999; 162:176–185.

    PubMed  CAS  Google Scholar 

  194. Simpson RJ, Hammacher A, Smith DK et al. Interleukin-6: Structure-function relationships. Protein Sci 1997; 6:929–955.

    PubMed  CAS  Google Scholar 

  195. Muller-Newen G, Kuster A, Wijdenes J et al. Studies on the interleukin-6-type cytokine signal transducer gpl30 reveal a novel mechanism of receptor activation by monoclonal antibodies. J Biol Chem 2000; 275:4579–4586.

    PubMed  CAS  Google Scholar 

  196. Autissier P, De Vos J, Liautard J et al. Dimerization and activation of the common transducing chain (gpl30) of the cytokines of the IL-6 family by mAb. Int Immunol 1998; 10:1881–1889.

    PubMed  CAS  Google Scholar 

  197. Chan KF, Siegel MR, Lenardo JM. Signaling by the TNF receptor superfamily and T-cell homeostasis. Immunity 2000; 13:419–422.

    PubMed  CAS  Google Scholar 

  198. Chan FK. Three is better than one: Preligand receptor assembly in the regulation of TNF receptor signaling. Cytokine 2007; 37:101–107.

    PubMed  CAS  Google Scholar 

  199. Siegers GM, Yang J, Duerr CU et al. Identification of disulfide bonds in the Ig-alpha/Ig-beta component of the B-cell antigen receptor using the Drosophila S2 cell reconstitution system. Int Immunol 2006; 18:1385–1396.

    PubMed  CAS  Google Scholar 

  200. Asai K, Fujimoto K, Harazaki M et al. Distinct aggregation of beta-and gamma-chains of the high-affinity IgE receptor on cross-hnking. J Histochem Cytochem 2000; 48:1705–1716.

    PubMed  CAS  Google Scholar 

  201. Siegel RM, Muppidi JR, Sarker M et al. SPOTS: signaling protein oligomeric transduction structures are early mediators of death receptor-induced apoptosis at the plasma membrane. J Cell Biol 2004; 167:735–744.

    PubMed  CAS  Google Scholar 

  202. Lee HK, Dunzendorfer S, Tobias PS. Cytoplasmic domain-mediated dimerizations of toll-like receptor 4 observed by beta-lactamase enzyme fragment complementation. J Biol Chem 2004; 279:10564–10574.

    PubMed  CAS  Google Scholar 

  203. Weber AN, Moncrieffe MC, Gangloff M et al. Ligand-receptor and receptor-receptor interactions act in concert to activate signaling in the Drosophila toll pathway. J Biol Chem 2005; 280:22793–22799.

    PubMed  CAS  Google Scholar 

  204. Kishimoto H, Kubo RT, Yorifuji H et al. Physical dissociation of the TCR-CD3 complex accompanies receptor ligation. J Exp Med 1995; 182:1997–2006.

    PubMed  CAS  Google Scholar 

  205. Kosugi A, Saitoh S, Noda S et al. Translocation of tyrosine-phosphorylated TCRzeta chain to glycolipidenriched membrane domains upon T-cell activation. Int Immunol 1999; 11:1395–1401.

    PubMed  CAS  Google Scholar 

  206. La Gruta NL, Liu H, Dilioglou S et al. Architectural changes in the TCR: CD3 complex induced by MHC: Peptide ligation. J Immunol 2004; 172:3662–3669.

    PubMed  Google Scholar 

  207. Liu H, Rhodes M, Wiest DL et al. On the dynamics of TCR: CD3 complex cell surface expression and downmodulation. Immunity 2000; 13:665–675.

    PubMed  CAS  Google Scholar 

  208. D'Oro U, Munitic I, Chacko G et al. Regulation of constitutive TCR internalization by the zeta-chain. J Immunol 2002; 169:6269–6278.

    PubMed  CAS  Google Scholar 

  209. McKay DB, Irie HY, Hollander G et al. Antigen-induced unresponsiveness results in altered T-cell signaling. J Immunol 1999; 163:6455–6461.

    PubMed  CAS  Google Scholar 

  210. Willems F, Andris F, Xu D et al. The induction of human T-cell unresponsiveness by soluble anti-CD3 mAb requires T-cell activation. Int Immunol 1995; 7:1593–1598.

    PubMed  CAS  Google Scholar 

  211. Wang XM, Djordjevic JT, Kurosaka N et al. T-cell antigen receptor peptides inhibit signal transduction within the membrane bilayer. Clin Immunol 2002; 105:199–207.

    PubMed  CAS  Google Scholar 

  212. Kim JH, Cramer L, Mueller H et al. Independent trafficking of Ig-alpha/Ig-beta and mu-heavy chain is facilitated by dissociation of the B-cell antigen receptor complex. J Immunol 2005; 175:147–154.

    PubMed  CAS  Google Scholar 

  213. Kremyanskaya M, Monroe JG. Ig-independent Ig beta expression on the surface of B lymphocytes after B-cell receptor aggregation. J Immunol 2005; 174:1501–1506.

    PubMed  CAS  Google Scholar 

  214. Davis MM, Boniface JJ, Reich Z et al. Ligand recognition by alpha beta T-cell receptors. Annu Rev Immunol 1998; 16:523–544.

    PubMed  CAS  Google Scholar 

  215. Gascoigne NR, Zal T, Alam SM. T-cell receptor binding kinetics in T-cell development and activation. Expert Rev Mol Med 2001; 2001:1–17.

    PubMed  Google Scholar 

  216. Germain RN, Stefanova I. The dynamics of T-cell receptor signaling: Complex orchestration and the key roles of tempo and cooperation. Annu Rev Immunol 1999; 17:467–522.

    PubMed  CAS  Google Scholar 

  217. Rosette C, Werlen G, Daniels MA et al. The impact of duration versus extent of TCR occupancy on T-cell activation: a revision of the kinetic proofreading model. Immunity 2001; 15:59–70.

    PubMed  CAS  Google Scholar 

  218. Werlen G, Hausmann B, Naeher D et al. Signaling life and death in the thymus: Timing is everything. Science 2003; 299:1859–1863.

    PubMed  CAS  Google Scholar 

  219. Love PE, Lee J, Shores EW. Critical relationship between TCR signaling potential and TCR affinity during thymocyte selection. J Immunol 2000; 165:3080–3087.

    PubMed  CAS  Google Scholar 

  220. Andersen PS, Geisler C, Buus S et al. Role of the T-cell receptor ligand affinity in T-cell activation by bacterial superantigens. J Biol Chem 2001; 276:33452–33457.

    PubMed  CAS  Google Scholar 

  221. Mirshahidi S, Ferris LC, Sadeg-Nasseri S. The magnitude of TCR engagement is a critical predictor of T-cell anergy or activation. J Immunol 2004; 172:5346–5355.

    PubMed  CAS  Google Scholar 

  222. Gett AV, Sallusto F, Lanzavecchia A et al. T-cell fitness determined by signal strength.Nat Immunol 2003; 4:355–360.

    PubMed  CAS  Google Scholar 

  223. Langenkamp A, Casorati G, Garavaglia C et al. T-cell priming by dendritic cells: Thresholds for proliferation, differentiation and death and intraclonal functional diversification. Eur J Immunol 2002; 32:2046–2054.

    PubMed  CAS  Google Scholar 

  224. Batista FD, Neuberger MS. Affinity dependence of the B-cell response to antigen: A threshold, a ceiling and the importance of off-rate. Immunity 1998; 8:751–759.

    PubMed  CAS  Google Scholar 

  225. Casola S, Otipoby KL, Alimzhanov M et al. B-cell receptor signal strength determines B-cell fate. Nat Immunol 2004; 5:317–327.

    PubMed  CAS  Google Scholar 

  226. Benschop RJ, Cambier JC. B-cell development: signal transduction by antigen receptors and their surrogates. Curr Opin Immunol 1999; 11:143–151.

    PubMed  CAS  Google Scholar 

  227. George J, Penner SJ, Weber J et al. Influence of membrane Ig receptor density and affinity on B-cell signaling by antigen. Implications for affinity maturation. J Immunol 1993; 151:5955–5965.

    PubMed  CAS  Google Scholar 

  228. Singh DK, Kumar D, Siddiqui Z et al. The strength of receptor signaling is centrally controlled through a cooperative loop between Ca2+ and an oxidant signal. Cell 2005; 121:281–293.

    PubMed  CAS  Google Scholar 

  229. Kinet JP. The high-affinity IgE receptor (Fc epsilon RI): From physiology to pathology. Annu Rev Immunol 1999; 17:931–972.

    PubMed  CAS  Google Scholar 

  230. Yamasaki S, Saito T. Regulation of mast cell activation through FcepsilonRI. Chem Immunol Allergy 2005; 87:22–31.

    PubMed  CAS  Google Scholar 

  231. Hlavacek WS, Redondo A, Wofsy C et al. Kinetic proofreading in receptor-mediated transduction of cellular signals: Receptor aggregation, partially activated receptors and cytosolic messengers. Bull Math Biol 2002; 64:887–911.

    PubMed  CAS  Google Scholar 

  232. Iwashima M. Kinetic perspectives of T-cell antigen receptor signaling. A two-tier model for T-cell full activation. Immunol Rev 2003; 191:196–210.

    PubMed  CAS  Google Scholar 

  233. Hlavacek WS, Redondo A, Metzger H et al. Kinetic proofreading models for cell signaling predict ways to escape kinetic proofreading. Proc Natl Acad Sci USA 2001; 98:7295–7300.

    PubMed  CAS  Google Scholar 

  234. Haefner J. Modeling Biological Systems: Principles and Applications, 2nd ed. New York: Springer; 2005:480.

    Google Scholar 

  235. Ono S, Ohno H, Saito T. Rapid turnover of the CD3 zeta chain independent of the TCR-CD3 complex in normal T-cells. Immunity 1995; 2:639–644.

    PubMed  CAS  Google Scholar 

  236. McKeithan TW. Kinetic proofreading in T-cell receptor signal transduction.Proc Natl Acad Sci USA 1995; 92:5042–5046.

    PubMed  CAS  Google Scholar 

  237. Rabinowitz JD, Beeson C, Lyons DS et al. Kinetic discrimination in T-cell activation. Proc Natl Acad Sci USA 1996; 93:1401–1405.

    PubMed  CAS  Google Scholar 

  238. Rabinowitz JD, Beeson C, Wulfing C et al. Altered T-cell receptor ligands trigger a subset of early T-cell signals. Immunity 1996; 5:125–135.

    PubMed  CAS  Google Scholar 

  239. Kersh GJ, Kersh EN, Fremont DH et al. High-and low-potency ligands with similar affinities for the TCR: the importance of kinetics in TCR signaling. Immunity 1998; 9:817–826.

    PubMed  CAS  Google Scholar 

  240. Schamel WW, Risueno RM, Minguet S et al. A conformation-and avidity-based proofreading mechanism for the TCR-CD3 complex. Trends Immunol 2006; 27:176–182.

    PubMed  CAS  Google Scholar 

  241. Valitutti S, Muller S, Cella M et al. Serial triggering of many T-cell receptors by a few peptide-MHC complexes. Nature 1995; 375:148–151.

    PubMed  CAS  Google Scholar 

  242. Itoh Y, Hemmer B, Martin R et al. Serial TCR engagement and down-modulation by peptide:MHC molecule ligands: relationship to the quality of individual TCR signaling events. J Immimol 1999; 162:2073–2080.

    CAS  Google Scholar 

  243. Borovsky Z, Misha-Eisenberg G, Yaniv E et al. Serial triggering of T-cell receptors results in incremental accumulation of signaling intermediates. J Biol Chem 2002; 277:21529–21536.

    PubMed  CAS  Google Scholar 

  244. Sousa J, Carneiro J. A mathematical analysis of TCR serial triggering and down-regulation. Eur J Immunol 2000; 30:3219–3227.

    PubMed  CAS  Google Scholar 

  245. Friedl P, Gunzer M. Interaction of T-cells with APCs: The serial encounter model.Trends Immunol 2001; 22:187–191.

    PubMed  CAS  Google Scholar 

  246. Davis MM. A new trigger for T-cells. Cell 2002; 110:285–287.

    PubMed  CAS  Google Scholar 

  247. Alarcon B, Gil D, Delgado P et al. Initiation of TCR signaling: Regulation within CD3 dimers. Immunol Rev 2003; 191:38–46.

    PubMed  CAS  Google Scholar 

  248. Reth M, Wienands J, Schamel WW. An unsolved problem of the clonal selection theory and the model of an oligomeric B-cell antigen receptor. Immunol Rev 2000; 176:10–18.

    PubMed  CAS  Google Scholar 

  249. Aivazian D, Stern LJ. Phosphorylation of T-cell receptor zeta is regulated by a lipid dependent folding transition. Nat Struct Biol 2000; 7:1023–1026.

    PubMed  CAS  Google Scholar 

  250. Rojo JM, Janeway CA Jr. The biologic activity of anti-T-cell receptor V region monoclonal antibodies is determined by the epitope recognized. J Immimol 1988; 140:1081–1088.

    CAS  Google Scholar 

  251. Krogsgaard M, Prado N, Adams EJ et al. Evidence that structural rearrangements and/or flexibility during TCR binding can contribute to T-cell activation. Mol Cell 2003; 12:1367–1378.

    PubMed  CAS  Google Scholar 

  252. Kjer-Nielsen L, Dunstone MA, Kostenko L et al. Crystal structure of the human T-cell receptor CD3 epsilon gamma heterodimer complexed to the therapeutic mAb OKT3. Proc Natl Acad Sci USA 2004; 101:7675–7680.

    PubMed  CAS  Google Scholar 

  253. Levin SE, Weiss A. Twisting tails exposed: The evidence for TCR conformational change.J Exp Med 2005; 201:489–492.

    PubMed  CAS  Google Scholar 

  254. Anton van der Merwe P, Davis SJ, Shaw AS et al. Cytoskcletal polarization and redistribution of cell-surface molecules during T-cell antigen recognition. Semin Immunol 2000; 12:5–21.

    Google Scholar 

  255. Monks CR, Freiberg BA, Kupfer H et al. Three-dimensional segregation of supramolecular activation clusters in T-cells. Nature 1998; 395:82–86.

    PubMed  CAS  Google Scholar 

  256. Davis SJ, van der Merwe PA. The kinetic-segregation model: TCR triggering and beyond. Nat Immunol 2006; 7:803–809.

    PubMed  CAS  Google Scholar 

  257. Manolios N, Collier S, Taylor J et al. T-cell antigen receptor transmembrane peptides modulate T-cell function and T-cell-mediated disease. Nat Med 1997; 3:84–88.

    PubMed  CAS  Google Scholar 

  258. Ali M, De Planque MRR, Huynh NT et al. Biophysical studies of a transmembrane peptide derived from the T-cell antigen receptor. Lett Pept Sci 2002; 8:227–233.

    Google Scholar 

  259. Bender V, Ali M, Amon M et al. T-cell antigen receptor peptide-lipid membrane interactions using surface plasmon resonance. J Biol Chem 2004; 279:54002–54007.

    PubMed  CAS  Google Scholar 

  260. Gerber D, Quintana FJ, Bloch I et al. D-enantiomer peptide of the TCRalpha transmembrane domain inhibits T-cell activation in vitro and in vivo. FASEB J 2005; 19:1190–1192.

    PubMed  CAS  Google Scholar 

  261. Enk AH, Knop J. T-cell receptor mimic peptides and their potential application in T-cell-mediated disease. Int Arch Allergy Immunol 2000; 123:275–281.

    PubMed  CAS  Google Scholar 

  262. GoUner GP, Muller G, Alt R et al. Therapeutic application of T-cell receptor mimic peptides or cDNA in the treatment of T-cell-mediated skin diseases. Gene Ther 2000; 7:1000–1004.

    Google Scholar 

  263. ManoUos N, Huynh NT, Collier S. Peptides in the treatment of inflammatory skin disease. Australas J Dermatol 2002; 43:226–227.

    PubMed  Google Scholar 

  264. Kurosaka N, Bolte A, Ali M et al. T-cell antigen receptor assembly and cell surface expression is not affected by treatment with T-cell antigen receptor-alpha chain transmembrane peptide. Protein Pept Lett 2007; 14:299–303.

    PubMed  CAS  Google Scholar 

  265. Collier S, Bolte A, Manolios N. Discrepancy in CD3-transmembrane peptide activity between in vitro and in vivo T-cell inhibition. Scand J Immunol 2006; 64:388–391.

    PubMed  CAS  Google Scholar 

  266. Amon MA, Ali M, Bender V et al. Lipidation and glycosylation of a T-cell antigen receptor (TCR) transmembrane hydrophobic peptide dramatically enhances in vitro and in vivo function. Biochim Biophys Acta 2006.

    Google Scholar 

  267. Ali M, Salam NK, Amon M et al. T-cell antigen receptor-alpha chain transmembrane peptides: Correlation between structure and function. Int J Pept Res Ther 2006; 12:261–267.

    CAS  Google Scholar 

  268. Vandebona H, Ali M, Amon M et al. Immunoreceptor transmembrane peptides and their effect on natural killer (NK) cell cytotoxicity. Protein Pept Lett 2006; 13:1017–1024.

    PubMed  CAS  Google Scholar 

  269. Sigalov AB. Interaction between HIV gp41 fusion peptide and T-cell receptor: Putting the puzzle pieces back together. FASEB J 2007; 21:1633–1634; author reply 1635.

    PubMed  CAS  Google Scholar 

  270. Spencer DM, Wandless TJ, Schreiber SL et al. Controlling signal transduction with synthetic ligands. Science 1993; 262:1019–1024.

    PubMed  CAS  Google Scholar 

  271. Soldevila G, Castellanos C, Malissen M et al. Analysis of the individual role of the TCRzeta chain in transgenic mice after conditional activation with chemical inducers of dimerization. Cell Immunol 2001; 214:123–138.

    PubMed  CAS  Google Scholar 

  272. Crabtree GR, Schreiber SL. Three-part inventions: Intracellular signaling and induced proximity. Trends Biochem Sci 1996; 21:418–422.

    PubMed  CAS  Google Scholar 

  273. Buferne M, Luton F, Letourneur F. eaet al. Role of CD3 delta in surface expression of the TCR/CD3 complex and in activation for killing analyzed with a CD3 delta-negative cytotoxic T-lymphocyte variant. J Immunol 1992; 148:657–

    Google Scholar 

  274. Luton F, Buferne M, Legendre V et al. Role of CD3gamma and CD3delta cytoplasmic domains in cytolytic T-lymphocyte functions and TCR/CD3 down-modulation. J Immunol 1997; 158:4162–4170.

    PubMed  CAS  Google Scholar 

  275. Haks MC, Cordaro TA, van den Brakel JH et al. A redundant role of the CD3 gamma-immunoreceptor tyrosine-based activation motif in mature T-cell function. J Immunol 2001; 166:2576–2588.

    PubMed  CAS  Google Scholar 

  276. Haks MC, Pepin E, van den Brakel JH et al. Contributions of the T-cell receptor-associated CD3gamma-ITAM to thymocyte selection. J Exp Med 2002; 196:1–13.

    PubMed  CAS  Google Scholar 

  277. de Saint Basile G, Geissmann F, Flori E et al. Severe combined immunodeficiency caused by deficiency in either the delta or the epsilon subunit of CD3. J Clin Invest 2004; 114:1512–1517.

    PubMed  Google Scholar 

  278. Roifman CM. CD3 delta immunodeficiency. Curr Opin Allergy Clin Immunol 2004; 4:479–484.

    PubMed  CAS  Google Scholar 

  279. Teixeiro E, Daniels MA, Hausmann B et al. T-cell division and death are segregated by mutation of TCRbeta chain constant domains. Immunity 2004; 21:515–526.

    PubMed  CAS  Google Scholar 

  280. Torres PS, Zapata DA, PachecoCastro A et al. Contribution of CD3 gamma to TCR regulation and signaling in human mature T-lymphocytes. Int Immunol 2002; 14:1357–1367.

    PubMed  CAS  Google Scholar 

  281. Rodriguez-Tarduchy G, Sahuquillo AG, Alarcon B et al. Apoptosis but not other activation events is inhibited by a mutation in the transmembrane domain of T-cell receptor beta that impairs CD3zeta association. J Biol Chem 1996; 271:30417–30425.

    PubMed  CAS  Google Scholar 

  282. Sutton BJ, Gould HJ. The human IgE network. Nature 1993; 366:421–428.

    PubMed  CAS  Google Scholar 

  283. Gould HJ, Sutton BJ, Beavil AJ et al. The biology of IGE and the basis of allergic disease. Annu Rev Immunol 2003; 21:579–628.

    PubMed  CAS  Google Scholar 

  284. Kraft S, Novak N. Fc receptors as determinants of allergic reactions. Trends Immunol 2006; 27:88–95.

    PubMed  CAS  Google Scholar 

  285. Adamczewski M, Paolini R, Kinet JP. Evidence for two distinct phosphorylation pathways activated by high affinity immunoglobulin E receptors. J Biol Chem 1992; 267:18126–18132.

    PubMed  CAS  Google Scholar 

  286. Dombrowicz D, Lin S, Flamand V et al. Allergy-associated FcRbeta is a molecular amplifier of IgE-and IgG-mediated in vivo responses. Immunity 1998; 8:517–529.

    PubMed  CAS  Google Scholar 

  287. Eiseman E, Bolen JB. Signal transduction by the cytoplasmic domains of Fc epsilon Rl-gamma and TCR-zeta in rat basophilic leukemia cells. J Biol Chem 1992; 267:21027–21032.

    PubMed  CAS  Google Scholar 

  288. Jouvin MH, Adamczewski M, Numerof R et al. Differential control of the tyrosine kinases Lyn and Syk by the two signaling chains of the high affinity immunoglobulin E receptor. J Biol Chem 1994; 269:5918–5925.

    PubMed  CAS  Google Scholar 

  289. Scharcnberg AM, Lin S, Cuenod B et al. Reconstitution of interactions between tyrosine kinases and the high affinity IgE receptor which are controlled by receptor clustering. EMBO J 1995; 14:3385–3394.

    Google Scholar 

  290. Shiue L, Green J, Green OM et al. Interaction of p72syk with the gamma and beta subunits of the high-affinity receptor for immunoglobulin E, Fc epsilon RI. Mol Cell Biol 1995; 15:272–281.

    PubMed  CAS  Google Scholar 

  291. Wilson BS, Kapp N, Lee RJ et al. Distinct functions of the Fc epsilon Rl gamma and beta subunits in the control of Fc epsilon Rl-mediated tyrosine kinase activation and signaling responses in RBL-2H3 mast cells. J Biol Chem 1995; 270:4013–4022.

    PubMed  CAS  Google Scholar 

  292. Goldstein B, Faeder JR, Hlavacek WS. Mathematical and computational models of immune-receptor signalling. Nat Rev Immunol 2004; 4:445–456.

    PubMed  CAS  Google Scholar 

  293. Goldstein B, Faeder JR, Hlavacek WS et al. Modeling the early signaling events mediated by FcepsilonRI. Mol Immunol 2002; 38:1213–1219.

    PubMed  CAS  Google Scholar 

  294. Faeder JR, Hlavacek WS, Reischl I et al. Investigation of early events in Fc epsilon Rl-mediated signaling using a detailed mathematical model. J Immunol 2003; 170:3769–3781.

    PubMed  CAS  Google Scholar 

  295. Hlavacek WS, Faeder JR, BUnov ML et al. The complexity of complexes in signal transduction. Biotechnol Bioeng 2003; 84:783–794.

    PubMed  CAS  Google Scholar 

  296. Nadler MJ, Matthews SA, Turner H et al. Signal transduction by the high-affinity immunoglobulin E receptor Fc epsilon RI: coupling form to function. Adv Immunol 2000; 76:325–355.

    PubMed  CAS  Google Scholar 

  297. Liu KJ, Parikh VS, Tucker PW et al. Role of the B-cell antigen receptor in antigen processing and presentation. Involvement of the transmembrane region in intracellular trafficking of receptor/ligand complexes. J Immunol 1993; 151:6143–6154.

    PubMed  CAS  Google Scholar 

  298. Pleiman CM, D’Ambrosio D, Cambier JC. The B-cell antigen receptor complex: Structure and signal transduction. Immunol Today 1994; 15:393–399.

    PubMed  CAS  Google Scholar 

  299. Cambier JC. Signal transduction by T-and B-cell antigen receptors: Converging: Structures and concepts. Curr Opin Immunol 1992; 4:257–264.

    PubMed  CAS  Google Scholar 

  300. Cambier JC, Pleiman CM, Clark MR. Signal transduction by the B-cell antigen receptor and its coreceptors. Annu Rev Immunol 1994; 12:457–486.

    PubMed  CAS  Google Scholar 

  301. Kraus M, Pao LI, Reichlin A et al. Interference with immunoglobulin (Ig) alpha immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation modulates or blocks B-cell development, depending on the availability of an Igbeta cytoplasmic tail. J Exp Med 2001; 194:455–469.

    PubMed  CAS  Google Scholar 

  302. Batista FD, Iber D, Neuberger MS. B-cells acquire antigen from target cells after synapse formation. Nature 2001; 411:489–494.

    PubMed  CAS  Google Scholar 

  303. Bannish G, Fuentes-Panana EM, Cambier JC et al. Ligand-independent signaling functions for the B-lymphocyte antigen receptor and their role in positive selection during B-lymphopoiesis. J Eiip Med 2001; 194:1583–1596.

    CAS  Google Scholar 

  304. Kato K, Kanaji T, Russell S et al. The contribution of glycoprotein VI to stable platelet adhesion and thrombus formation illustrated by targeted gene deletion. Blood 2003; 102:1701–1707.

    PubMed  CAS  Google Scholar 

  305. Gawaz M. Role of platelets in coronary thrombosis and reperfusion of ischemic myocardium. Cardiovasc Res 2004; 61:498–511.

    PubMed  CAS  Google Scholar 

  306. Gibbins JM, Okuma M, Farndale R et al. Glycoprotein VI is the collagen receptor in platelets which underlies tyrosine phosphorylation of the Fc receptor gamma-chain. FEBS Lett 1997; 413:255–259.

    PubMed  CAS  Google Scholar 

  307. Sigalov AB. More on: glycoprotein VI oligomerization: A novel concept of platelet inhibition. J Thromb Haemost 2007; 5:2310–2312.

    PubMed  CAS  Google Scholar 

  308. Sigalov AB. Inhibiting Collagen-induced Platelet Aggregation and Activation with Peptide Variants. US 12/001,258 and PCT PCT/US2007/025389 patent applications were filed on 12/11/2007 and 12/12/2007, respectively, claiming a priority to US provisional patent application 60/874,694 filed on 12/13/2006.

    Google Scholar 

  309. Leitenberg D, Balamuth F, Bottomly K. Changes in the T-cell receptor macromolecular signaling complex and membrane microdomains during T-cell development and activation. Semin Immunol 2001; 13:129–138.

    PubMed  CAS  Google Scholar 

  310. Janeway CA Jr, Bottomly K. Responses of T-cells to ligands for the T-cell receptor.Semin Immunol 1996; 8:108–115.

    PubMed  Google Scholar 

  311. Janeway CA Jr, Bottomly K. Signals and signs for lymphocyte responses. Cell 1994; 76:275–285.

    PubMed  CAS  Google Scholar 

  312. Niedergang F, Dautry-Varsat A, Alcover A. Peptide antigen or superantigen-induced down-regulation of TCRs involves both stimulated and unstimulated receptors. J Immunol 1997; 159:1703–1710.

    PubMed  CAS  Google Scholar 

  313. Bonefeld CM, Rasmussen AB, Lauritsen JP et al. TCR comodulation of nonengaged TCR takes place by a protein kinase C and CD3 gamma di-leucine-based motif-dependent mechanism. J Immunol 2003; 171:3003–3009.

    PubMed  CAS  Google Scholar 

  314. San Jose E, Borroto A, Niedergang F et al. Triggering the TCR complex causes the downregulation of nonengaged receptors by a signal transduction-dependent mechanism. Immunity 2000; 12:161–170.

    PubMed  CAS  Google Scholar 

  315. von Essen M, Nielsen MW, Bonefeld CM et al. Protein kinase C (PKC) alpha and PKC theta are the major PKC isotypes involved in TCR down-regulation. J Immunol 2006; 176:7502–7510.

    Google Scholar 

  316. Quintana FJ, Gerber D, Kent SC et al. HIV-1 fusion peptide targets the TCR and inhibits antigen-specific T-cell activation. J Clin Invest 2005; 115:2149–2158.

    PubMed  CAS  Google Scholar 

  317. Bloch I, Quintana FJ, Gerber D et al. T-Cell inactivation and immunosuppressive activity induced by HIV gp41 via novel interacting motif. FASEB J 2007; 21:393–401.

    PubMed  CAS  Google Scholar 

  318. Alarcon B, Swamy M, van Santen HM et al. T-cell antigen-receptor stoichiometry: Preclustering for sensitivity. EMBO Rep 2006; 7:490–495.

    PubMed  CAS  Google Scholar 

  319. Kim YM, Pan JY, Korbel GA et al. Monovalent ligation of the B-cell receptor induces receptor activation but fails to promote antigen presentation. Proc Natl Acad Sci USA 2006; 103:3327–3332.

    PubMed  CAS  Google Scholar 

  320. Eynon EE, Parker DC. Small B-cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J Exp Med 1992; 175:131–138.

    PubMed  CAS  Google Scholar 

  321. Gahring LC, Weigle WO. The induction of peripheral T-cell unresponsiveness in adult mice by monomeric human gamma-globulin. J Immimol 1989; 143:2094–2100.

    CAS  Google Scholar 

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  1. Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, 01655, MA, USA

    Alexander B. Sigalov

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Sigalov, A.B. (2008). Signaling Chain Homooligomerization (SCHOOL) Model. In: Sigalov, A.B. (eds) Multichain Immune Recognition Receptor Signaling. Advances in Experimental Medicine and Biology, vol 640. Springer, New York, NY. https://doi.org/10.1007/978-0-387-09789-3_12

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