Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The kinetic-segregation model: TCR triggering and beyond

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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

References

  1. 1

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

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  22. 22

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  31. 31

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

    CAS  Article  Google Scholar 

  32. 32

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  41. 41

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

    CAS  Article  Google Scholar 

  42. 42

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

    CAS  Article  Google Scholar 

  43. 43

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  46. 46

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

    CAS  Article  Google Scholar 

  47. 47

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  50. 50

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  53. 53

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  61. 61

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

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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

Author information

Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Video 1

An annotated FLASH animation illustrating the KS model (this can also be seen at www.t-cellbiology.org/ks_model). (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 www.t-cellbiology.org/antibody). (MOV 1538 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing