A role for differential variable gene pairing in creating T cell receptors specific for unique major histocompatibility ligands

Immunity. 2011 Nov 23;35(5):694-704. doi: 10.1016/j.immuni.2011.10.012.


A limited set of T cell receptor (TCR) variable (V) gene segments are used to create a repertoire of TCRs that recognize all major histocompatibility complex (MHC) ligands within a species. How individual αβTCRs are constructed to specifically recognize a limited set of MHC ligands is unclear. Here we have identified a role for the differential pairing of particular V gene segments in creating TCRs that recognized MHC class II ligands exclusively, or cross-reacted with classical and nonclassical MHC class I ligands. Biophysical and structural experiments indicated that TCR specificity for MHC ligands is not driven by germline-encoded pairwise interactions.Rather, identical TCRβ chains can have altered peptide-MHC (pMHC) binding modes when paired with different TCRα chains. The ability of TCR chain pairing to modify how V region residues interact with pMHC helps to explain how the same V genes are used to create TCRs specific for unique MHC ligands.

Publication types

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

MeSH terms

  • Animals
  • Cross Reactions / immunology
  • Histocompatibility Antigens / chemistry*
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Molecular
  • Peptides / chemistry
  • Peptides / immunology
  • Peptides / metabolism
  • Protein Binding / immunology
  • Protein Conformation
  • Receptors, Antigen, T-Cell, alpha-beta / chemistry
  • Receptors, Antigen, T-Cell, alpha-beta / genetics*
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Thymus Gland / immunology
  • Thymus Gland / metabolism


  • Histocompatibility Antigens
  • Ligands
  • Peptides
  • Receptors, Antigen, T-Cell, alpha-beta

Associated data

  • PDB/3RDT