Canonical T cell receptor docking on peptide-MHC is essential for T cell signaling

Science. 2021 Jun 4;372(6546):eabe9124. doi: 10.1126/science.abe9124.


T cell receptor (TCR) recognition of peptide-major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using "reversed-docking" TCRβ-variable (TRBV) 17+ TCRs from the naïve mouse CD8+ T cell repertoire that recognizes the H-2Db-NP366 epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR-pMHCI binding or clustering characteristics. Canonical TCR-pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR-pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR-pMHC docking topology is mandated by T cell signaling constraints.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD3 Complex / metabolism
  • CD8 Antigens / immunology
  • CD8 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Epitopes, T-Lymphocyte
  • Female
  • Histocompatibility Antigen H-2D / chemistry
  • Histocompatibility Antigen H-2D / immunology
  • Histocompatibility Antigen H-2D / metabolism*
  • Influenza A virus
  • Lymphocyte Activation
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Major Histocompatibility Complex
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Nucleocapsid Proteins / chemistry
  • Nucleocapsid Proteins / immunology
  • Nucleocapsid Proteins / metabolism*
  • Orthomyxoviridae Infections / immunology*
  • Peptide Fragments / immunology
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Conformation
  • Receptors, Antigen, T-Cell, alpha-beta / chemistry
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • Signal Transduction


  • CD3 Complex
  • CD8 Antigens
  • Epitopes, T-Lymphocyte
  • Histocompatibility Antigen H-2D
  • NP protein, Influenza A virus
  • Nucleocapsid Proteins
  • Peptide Fragments
  • Receptors, Antigen, T-Cell, alpha-beta
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)