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.
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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)
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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
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