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

Nature. 2005 Jul 28;436(7050):578-82. doi: 10.1038/nature03843.


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 responses. The mechanism by which TCR-pMHC ligation initiates signalling, a process termed TCR triggering, remains controversial. It has been proposed 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Antigens / chemistry
  • Antigens / immunology
  • CHO Cells
  • Cattle
  • Cell Line
  • Cricetinae
  • Histocompatibility Antigens / immunology
  • Histocompatibility Antigens / metabolism*
  • Kinetics
  • Leukocyte Common Antigens / immunology
  • Leukocyte Common Antigens / metabolism
  • Ligands
  • Lymphocyte Activation*
  • Peptides / chemistry*
  • Peptides / immunology*
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell / chemistry
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*


  • Antigens
  • Histocompatibility Antigens
  • Ligands
  • Peptides
  • Receptors, Antigen, T-Cell
  • Leukocyte Common Antigens