The kinetic-segregation model: TCR triggering and beyond

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How the T cell receptor engages antigen is known, but not how that 'triggers' intracellular signaling. The first direct support for a mechanism based on the spatial reorganization of signaling proteins, proposed 10 years ago and referred to as the 'kinetic-segregation' model, is now beginning to emerge, along with indications that it may also apply to the triggering of nonclonotypic receptors. We describe here the development of the model, review new data and suggest how the model fits a broader conceptual framework for receptor triggering. We also consider the capacity of the model, versus that of other proposals, to account for the established features of TCR triggering.

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Figure 1: The KS model.
Figure 2: Evidence supporting the KS model.
Figure 3: Broad implications of the KS model.


  1. 1

    Dobzhansky, T. Nothing in biology makes sense except in the light of evolution. Am. Biol. Teach. 35, 125–129 (1973).

  2. 2

    Garcia, K.C. et al. An αβ T cell receptor structure at 2.5 Å and its orientation in the TCR-MHC complex. Science 274, 209–219 (1996).

  3. 3

    Garboczi, D.N. et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 384, 134–141 (1996).

  4. 4

    Adams, E.J., Chien, Y.H. & Garcia, K.C. Structure of a γδ T cell receptor in complex with the nonclassical MHC T22. Science 308, 227–231 (2005).

  5. 5

    Glaeser, R.M., Baldwin, J., Ceska, T.A. & Henderson, R. Electron diffraction analysis of the M412 intermediate of bacteriorhodopsin. Biophys. J. 50, 913–920 (1986).

  6. 6

    Ullrich, A. & Schlessinger, J. Signal transduction by receptors with tyrosine kinase activity. Cell 61, 203–212 (1990).

  7. 7

    Williams, A.F. & Beyers, A.D. T-cell receptors. At grips with interactions. Nature 356, 746–747 (1992).

  8. 8

    O'Rourke, A.M., Rogers, J. & Mescher, M.F. Activated CD8 binding to class I protein mediated by the T-cell receptor results in signaling. Nature 346, 187–189 (1990).

  9. 9

    Mittler, R.S., Goldman, S.J., Spitalny, G.L. & Burakoff, S.J. T-cell receptor-CD4 physical association in a murine T-cell hybridoma: induction by antigen receptor ligation. Proc. Natl. Acad. Sci. USA 86, 8531–8535 (1989).

  10. 10

    Xu, H. & Littman, D.R. A kinase-independent function of Lck in potentiating antigen-specific T cell activation. Cell 74, 633–643 (1993).

  11. 11

    Springer, T.A. Adhesion receptors of the immune system. Nature 346, 425–434 (1990).

  12. 12

    van der Merwe, P.A., McNamee, P.N., Davies, E.A., Barclay, A.N. & Davis, S.J. Topology of the CD2–CD48 cell-adhesion molecule complex: implications for antigen recognition by T cells. Curr. Biol. 5, 74–84 (1995).

  13. 13

    Secrist, J.P., Burns, L.A., Karnitz, L., Koretzky, G.A. & Abraham, R.T. Stimulatory effects of the protein tyrosine phosphatase inhibitor, pervanadate, on T-cell activation events. J. Biol. Chem. 268, 5886–5893 (1993).

  14. 14

    Mustelin, T., Coggeshall, K.M. & Altman, A. Rapid activation of the T-cell tyrosine protein kinase Lck by the CD45 phosphotyrosine phosphatase. Proc. Natl. Acad. Sci. USA 86, 6302–6306 (1989).

  15. 15

    Trowbridge, I.S. & Thomas, M.L. CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. Annu. Rev. Immunol. 12, 85–116 (1994).

  16. 16

    Davis, S.J. & van der Merwe, P.A. The structure and ligand interactions of CD2: implications for T-cell function. Immunol. Today 17, 177–187 (1996).

  17. 17

    van der Merwe, P.A., Davis, S.J., Shaw, A.S. & Dustin, M.L. Cytoskeletal polarization and redistribution of cell-surface molecules during T cell antigen recognition. Semin. Immunol. 12, 5–21 (2000).

  18. 18

    Dustin, M.L. et al. A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell 94, 667–677 (1998).

  19. 19

    Shaw, A.S. & Dustin, M.L. Making the T cell receptor go the distance: a topological view of T cell activation. Immunity 6, 361–369 (1997).

  20. 20

    Burroughs, N.J., Lazic, Z. & van der Merwe, P.A. Ligand detection and discrimination by spatial localization: a kinase-phosphatase segregation model of TCR activation. Biophys. J. (in the press) (2006).

  21. 21

    McKeithan, T.W. Kinetic proofreading in T-cell receptor signal transduction. Proc. Natl. Acad. Sci. USA 92, 5042–5046 (1995).

  22. 22

    Lee, K.H. et al. The immunological synapse balances T cell receptor signaling and degradation. Science 302, 1218–1222 (2003).

  23. 23

    Yokosuka, T. et al. Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nat. Immunol. 6, 1253–1262 (2005).

  24. 24

    Varma, R., Campi, G., Yokosuka, T., Saito, T. & Dustin, M.L. Compartmentalization of signaling and degradation in the immunological synapse. Immunity (in the press).

  25. 25

    Monks, C.R., Freiberg, B.A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998).

  26. 26

    Grakoui, A. et al. The immunological synapse: A molecular machine controlling T cell activation. Science 285, 221–227 (1999).

  27. 27

    Sperling, A.I. et al. TCR signaling induces selective exclusion of CD43 from the T cell-antigen-presenting cell contact site. J. Immunol. 161, 6459–6462 (1998).

  28. 28

    Johnson, K.G., Bromley, S.K., Dustin, M.L. & Thomas, M.L. A supramolecular basis for CD45 tyrosine phosphatase regulation in sustained T cell activation. Proc. Natl. Acad. Sci. USA 97, 10138–10143 (2000).

  29. 29

    Leupin, O., Zaru, R., Laroche, T., Muller, S. & Valitutti, S. Exclusion of CD45 from the T-cell receptor signaling area in antigen-stimulated T lymphocytes. Curr. Biol. 10, 277–280 (2000).

  30. 30

    Lin, J. & Weiss, A. The tyrosine phosphatase CD148 is excluded from the immunologic synapse and down-regulates prolonged T cell signaling. J. Cell Biol. 162, 673–682 (2003).

  31. 31

    Freiberg, B.A. et al. Staging and resetting T cell activation in SMACs. Nat. Immunol. 3, 911–917 (2002).

  32. 32

    Lee, K.H. et al. T cell receptor signaling precedes immunological synapse formation. Science 295, 1539–1542 (2002).

  33. 33

    Campi, G., Varma, R. & Dustin, M.L. Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. J. Exp. Med. 202, 1031–1036 (2005).

  34. 34

    Bunnell, S.C. et al. T cell receptor ligation induces the formation of dynamically regulated signaling assemblies. J. Cell Biol. 158, 1263–1275 (2002).

  35. 35

    Irles, C. et al. CD45 ectodomain controls interaction with GEMs and Lck activity for optimal TCR signaling. Nat. Immunol. 4, 189–197 (2003).

  36. 36

    Choudhuri, K., Wiseman, D., Brown, M.H., Gould, K. & van der Merwe, P.A. T cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand. Nature 436, 578–582 (2005).

  37. 37

    van Wauwe, J.P., De Mey, J.R. & Goossens, J.G. OKT3: a monoclonal anti-human T lymphocyte antibody with potent mitogenic properties. J. Immunol. 124, 2708–2713 (1980).

  38. 38

    Siefken, R., Kurrle, R. & Schwinzer, R. CD28-mediated activation of resting human T cells without costimulation of the CD3/TCR complex. Cell. Immunol. 176, 59–65 (1997).

  39. 39

    Tacke, M., Hanke, G., Hanke, T. & Hunig, T. CD28-mediated induction of proliferation in resting T cells in vitro and in vivo without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. Eur. J. Immunol. 27, 239–247 (1997).

  40. 40

    Lühder, F. et al. Topological requirements and signaling properties of T cell-activating, anti-CD28 antibody superagonists. J. Exp. Med. 197, 955–966 (2003).

  41. 41

    Evans, E.J. et al. Crystal structure of a soluble CD28-Fab complex. Nat. Immunol. 6, 271–279 (2005).

  42. 42

    Alonso, A. et al. Protein tyrosine phosphatases in the human genome. Cell 117, 699–711 (2004).

  43. 43

    Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000).

  44. 44

    van Oers, N.S., Killeen, N. & Weiss, A. ZAP70 is constitutively associated with tyrosine-phosphorylated TCRζ in murine thymocytes and lymph node T cells. Immunity 1, 675–685 (1994).

  45. 45

    Choudhuri, A., Kearney, A., Bakker, T.R. & van der Merwe, P.A. Immunology: how do T cells recognize antigen? Curr. Biol. 15, R382–R385 (2005).

  46. 46

    van der Merwe, P. The TCR triggering puzzle. Immunity 14, 665–668 (2001).

  47. 47

    Krogsgaard, M. & Davis, M.M. How T cells 'see' antigen. Nat. Immunol. 6, 239–245 (2005).

  48. 48

    Kuhns, M.S., Davis, M.M. & Garcia, K.C. Deconstructing the form and function of the TCR/CD3 complex. Immunity 24, 133–139 (2006).

  49. 49

    Schamel, W.W., Risueno, R.M., Minguet, S., Ortiz, A.R. & Alarcon, B. A conformation- and avidity-based proofreading mechanism for the TCR-CD3 complex. Trends Immunol. 27, 176–182 (2006).

  50. 50

    Trautmann, A. & Randriamampita, C. Initiation of TCR signaling revisited. Trends Immunol. 24, 425–428 (2003).

  51. 51

    Locksley, R.M., Reiner, S.L., Hatam, F., Littman, D.R. & Killeen, N. Helper T cells without CD4: control of Leishmaniasis in CD4-deficient mice. Science 261, 1448–1451 (1993).

  52. 52

    Schilham, M.W. et al. Alloreactive cytotoxic T cells can develop and function in mice lacking both CD4 and CD8. Eur. J. Immunol. 23, 1299–1304 (1993).

  53. 53

    Krogsgaard, M. et al. Agonist/endogenous peptide-MHC heterodimers drive T cell activation and sensitivity. Nature 434, 238–243 (2005).

  54. 54

    Sporri, R. & Reis e Sousa, C. Self peptide/MHC class I complexes have a negligible effect on the response of some CD8+ T cells to foreign antigen. Eur. J. Immunol. 32, 3161–3170 (2002).

  55. 55

    Szymczak, A.L. et al. The CD3epsilon proline-rich sequence, and its interaction with Nck, is not required for T cell development and function. J. Immunol. 175, 270–275 (2005).

  56. 56

    Chikuma, S., Abbas, A.K. & Bluestone, J.A. B7-independent inhibition of T cells by CTLA-4. J. Immunol. 175, 177–181 (2005).

  57. 57

    Vijayakrishnan, L. et al. An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells. Immunity 20, 563–575 (2004).

  58. 58

    Douglass, A.D. & Vale, R.D. Single-molecule microscopy reveals plasma membrane microdomains created by protein-protein networks that exclude or trap signaling molecules in T cells. Cell 121, 937–950 (2005).

  59. 59

    Staub, E., Rosenthal, A. & Hinzmann, B. Systematic identification of immunoreceptor tyrosine-based inhibitory motifs in the human proteome. Cell. Signal. 16, 435–456 (2004).

  60. 60

    Irvine, D.J., Purbhoo, M.A., Krogsgaard, M. & Davis, M.M. Direct observation of ligand recognition by T cells. Nature 419, 845–849 (2002).

  61. 61

    Davis, S.J. & van der Merwe, P.A. TCR triggering: co-receptor-dependent or -independent? Trends Immunol. 24, 624–626 (2003).

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We thank our colleagues for discussions and criticism. Supported by The Wellcome Trust and the United Kingdom Medical Research Council.

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Supplementary information

Supplementary Video 1

An annotated FLASH animation illustrating the KS model (this can also be seen at (MOV 4049 kb)

Supplementary Video 2

An annotated FLASH animation showing how the model can be extended to explain signaling by conventional and superagonistic antibodies (this can also be seen at (MOV 1538 kb)

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Davis, S., van der Merwe, P. The kinetic-segregation model: TCR triggering and beyond. Nat Immunol 7, 803–809 (2006) doi:10.1038/ni1369

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