T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand

Article metrics

Abstract

The binding of a T-cell antigen receptor (TCR) to peptide antigen presented by major histocompatibility antigens (pMHC) on antigen-presenting cells (APCs) is a central event in adaptive immune responses1,2. The mechanism by which TCR–pMHC ligation initiates signalling, a process termed TCR triggering, remains controversial3,4,5. It has been proposed6,7,8 that TCR triggering is promoted by segregation at the T cell–APC interface of cell-surface molecules with small ectodomains (such as TCR–pMHC and accessory receptors) from molecules with large ectodomains (such as the receptor protein tyrosine phosphatases CD45 and CD148). Here we show that increasing the dimensions of the TCR–pMHC interaction by elongating the pMHC ectodomain greatly reduces TCR triggering without affecting TCR–pMHC ligation. A similar dependence on receptor–ligand complex dimensions was observed with artificial TCR–ligand systems that span the same dimensions as the TCR–pMHC complex. Interfaces between T cells and APCs expressing elongated pMHC showed an increased intermembrane separation distance and less depletion of CD45. These results show the importance of the small size of the TCR–pMHC complex and support a role for size-based segregation of cell-surface molecules in 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: Effect of elongating the SCT ectodomain on T-cell triggering.
Figure 2: Elongated SCT increases intermembrane distance and allows increased access of CD45 to the T-cell–APC interface.
Figure 3: Triggering in an artificial TCR–pMHC system is also dependent on ectodomain size.
Figure 4: Kinetic-segregation (K-S) model of TCR triggering6,7.

References

  1. 1

    van der Merwe, P. A. & Davis, S. J. Molecular interactions mediating T cell antigen recognition. Annu. Rev. Immunol. 21, 659–684 (2003)

  2. 2

    Davis, M. M. et al. Dynamics of cell surface molecules during T cell recognition. Annu. Rev. Biochem. 72, 717–742 (2003)

  3. 3

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

  4. 4

    Davis, M. M. A new trigger for T cells. Cell 110, 285–287 (2002)

  5. 5

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

  6. 6

    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)

  7. 7

    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)

  8. 8

    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)

  9. 9

    Weiss, A. & Samelson, L. E. in Fundamental Immunology (ed. Paul, W. E.) 321–364 (Lippincott Williams & Wilkins, Philadelphia, 2003)

  10. 10

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

  11. 11

    Barclay, A. N. et al. The Leucocyte Antigen Factsbook (Academic, London, 1997)

  12. 12

    Yu, Y. Y., Netuschil, N., Lybarger, L., Connolly, J. M. & Hansen, T. H. Cutting edge: single-chain trimers of MHC class I molecules form stable structures that potently stimulate antigen-specific T cells and B cells. J. Immunol. 168, 3145–3149 (2002)

  13. 13

    Cresswell, P., Bangia, N., Dick, T. & Diedrich, G. The nature of the MHC class I peptide loading complex. Immunol. Rev. 172, 21–28 (1999)

  14. 14

    Porgador, A., Yewdell, J. W., Deng, Y., Bennink, J. R. & Germain, R. N. Localization, quantitation, and in situ detection of specific peptide-MHC class I complexes using a monoclonal antibody. Immunity 6, 715–726 (1997)

  15. 15

    Dillon, S. R., Jameson, S. C. & Fink, P. J. V beta 5 + T cell receptors skew toward OVA + H-2Kb recognition. J. Immunol. 152, 1790–1801 (1994)

  16. 16

    Kersh, E. N., Shaw, A. S. & Allen, P. M. Fidelity of T cell activation through multistep T cell receptor ζ phosphorylation. Science 281, 572–575 (1998)

  17. 17

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

  18. 18

    Garcia, K. C. et al. Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science 279, 1166–1172 (1998)

  19. 19

    Wild, M. K. et al. Dependence of T cell antigen recognition on the dimensions of an accessory receptor-ligand complex. J. Exp. Med. 190, 31–41 (1999)

  20. 20

    Chan, P.-Y. & Springer, T. S. Effect of lengthening lymphocyte function-associated antigen 3 on adhesion to CD2. Mol. Biol. Cell 3, 157–166 (1992)

  21. 21

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

  22. 22

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

  23. 23

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

  24. 24

    Davis, D. M. et al. The human natural killer cell immune synapse. Proc. Natl Acad. Sci. USA 96, 15062–15067 (1999)

  25. 25

    Coombs, D., Dembo, M., Wofsy, C. & Goldstein, B. Equilibrium thermodynamics of cell-cell adhesion mediated by multiple ligand-receptor pairs. Biophys. J. 86, 1408–1423 (2004)

  26. 26

    Gil, D., Schamel, W. W., Montoya, M., Sanchez-Madrid, F. & Alarcon, B. Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signalling and synapse formation. Cell 109, 901–912 (2002)

  27. 27

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

  28. 28

    Davis, S. J. et al. The nature of molecular recognition by T cells. Nature Immunol. 4, 217–224 (2003)

  29. 29

    Greenwald, R. J., Freeman, G. J. & Sharpe, A. H. The B7 family revisited. Annu. Rev. Immunol. 23, 515–548 (2005)

  30. 30

    Lanier, L. L. NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005)

Download references

Acknowledgements

We thank P. Bowness for providing TCRζ template, R. Germain for the gift of antibody 25-D1.16, T. Elliott for T18 antiserum, N. Shastri for permission to use the B3Z hybridoma, C. Reis e Sousa for providing the B3Z hybridoma, M. Merkenschlager for spleens from OT-1 mice, N. Rust for assistance with cell sorting and M. Shaw for assistance with EM imaging. We thank N. Barclay, S. Davis and members of the van der Merwe laboratory for valuable discussion and advice. This work was supported by the Medical Research Council (P.A.v.d.M., D.W. and M.H.B.) and the Wellcome Trust (K.C. and K.G.).

Author information

Correspondence to Keith Gould or P. Anton van der Merwe.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Methods

Full details of experimental methods. (PDF 106 kb)

Supplementary Figure S1

Comparison of stimulation efficiency of SCT and SCD with exogenously added OVA peptide (pOVA-SCD). (PDF 56 kb)

Supplementary Figure S2

Expression of high levels of SCT /elongated SCTs and stimulation of OT1 CD8+ T-cells. (PDF 77 kb)

Supplementary Figure S3

Activation of B3Z T-hybridoma by CHO APCs expressing low levels of SCTs. (PDF 70 kb)

Supplementary Figure S4

Effect of elongation of the SCT ectodomain on TCR/SCT engagement. (PDF 113 kb)

Supplementary Figure S5

Distribution of CD45 at the B3Z/SCT-expressing APC interface. (PDF 58 kb)

Supplementary Figure S6

Characterization of artificial TCR triggering systems and their interaction with native and extended ligands. (PDF 68 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Choudhuri, K., Wiseman, D., Brown, M. et al. T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand. Nature 436, 578–582 (2005) doi:10.1038/nature03843

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.