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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
van der Merwe, P. A. & Davis, S. J. Molecular interactions mediating T cell antigen recognition. Annu. Rev. Immunol. 21, 659–684 (2003)
Davis, M. M. et al. Dynamics of cell surface molecules during T cell recognition. Annu. Rev. Biochem. 72, 717–742 (2003)
van der Merwe, P. The TCR triggering puzzle. Immunity 14, 665–668 (2001)
Davis, M. M. A new trigger for T cells. Cell 110, 285–287 (2002)
Trautmann, A. & Randriamampita, C. Initiation of TCR signalling revisited. Trends Immunol. 24, 425–428 (2003)
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)
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)
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)
Weiss, A. & Samelson, L. E. in Fundamental Immunology (ed. Paul, W. E.) 321–364 (Lippincott Williams & Wilkins, Philadelphia, 2003)
Springer, T. A. Adhesion receptors of the immune system. Nature 346, 425–434 (1990)
Barclay, A. N. et al. The Leucocyte Antigen Factsbook (Academic, London, 1997)
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)
Cresswell, P., Bangia, N., Dick, T. & Diedrich, G. The nature of the MHC class I peptide loading complex. Immunol. Rev. 172, 21–28 (1999)
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)
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)
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)
Garboczi, D. N. et al. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 384, 134–141 (1996)
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)
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)
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)
Irles, C. et al. CD45 ectodomain controls interaction with GEMs and Lck activity for optimal TCR signalling. Nature Immunol. 4, 189–197 (2003)
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)
Dustin, M. L. et al. A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell 94, 667–677 (1998)
Davis, D. M. et al. The human natural killer cell immune synapse. Proc. Natl Acad. Sci. USA 96, 15062–15067 (1999)
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)
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)
Krogsgaard, M. et al. Agonist/endogenous peptide–MHC heterodimers drive T cell activation and sensitivity. Nature 434, 238–243 (2005)
Davis, S. J. et al. The nature of molecular recognition by T cells. Nature Immunol. 4, 217–224 (2003)
Greenwald, R. J., Freeman, G. J. & Sharpe, A. H. The B7 family revisited. Annu. Rev. Immunol. 23, 515–548 (2005)
Lanier, L. L. NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005)
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.).
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Full details of experimental methods. (PDF 106 kb)
Comparison of stimulation efficiency of SCT and SCD with exogenously added OVA peptide (pOVA-SCD). (PDF 56 kb)
Expression of high levels of SCT /elongated SCTs and stimulation of OT1 CD8+ T-cells. (PDF 77 kb)
Activation of B3Z T-hybridoma by CHO APCs expressing low levels of SCTs. (PDF 70 kb)
Effect of elongation of the SCT ectodomain on TCR/SCT engagement. (PDF 113 kb)
Distribution of CD45 at the B3Z/SCT-expressing APC interface. (PDF 58 kb)
Characterization of artificial TCR triggering systems and their interaction with native and extended ligands. (PDF 68 kb)
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). https://doi.org/10.1038/nature03843
Current Opinion in Solid State and Materials Science (2021)
Science Immunology (2021)
Physics Reports (2020)
Frontiers in Cell and Developmental Biology (2020)