The T cell receptor's alpha-chain connecting peptide motif promotes close approximation of the CD8 coreceptor allowing efficient signal initiation

J Immunol. 2008 Jun 15;180(12):8211-21. doi: 10.4049/jimmunol.180.12.8211.


The CD8 coreceptor contributes to the recognition of peptide-MHC (pMHC) ligands by stabilizing the TCR-pMHC interaction and enabling efficient signaling initiation. It is unclear though, which structural elements of the TCR ensure a productive association of the coreceptor. The alpha-chain connecting peptide motif (alpha-CPM) is a highly conserved sequence of eight amino acids in the membrane proximal region of the TCR alpha-chain. TCRs lacking the alpha-CPM respond poorly to low-affinity pMHC ligands and are unable to induce positive thymic selection. In this study we show that CD8 participation in ligand binding is compromised in T lineage cells expressing mutant alpha-CPM TCRs, leading to a slight reduction in apparent affinity; however, this by itself does not explain the thymic selection defect. By fluorescence resonance energy transfer microscopy, we found that TCR-CD8 association was compromised for TCRs lacking the alpha-CPM. Although high-affinity (negative-selecting) pMHC ligands showed reduced TCR-CD8 interaction, low-affinity (positive-selecting) ligands completely failed to induce molecular approximation of the TCR and its coreceptor. Therefore, the alpha-CPM of a TCR is an important element in mediating CD8 approximation and signal initiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / genetics
  • Animals
  • CD8 Antigens / chemistry
  • CD8 Antigens / metabolism*
  • CD8 Antigens / physiology*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cell Line
  • Humans
  • Hybridomas
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Organ Culture Techniques
  • Peptide Fragments / chemistry
  • Peptide Fragments / physiology*
  • Receptors, Antigen, T-Cell, alpha-beta / chemistry
  • Receptors, Antigen, T-Cell, alpha-beta / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism


  • CD8 Antigens
  • CD8 antigen, alpha chain
  • CD8alphabeta antigen
  • Peptide Fragments
  • Receptors, Antigen, T-Cell, alpha-beta