T cell receptor cross-reactivity directed by antigen-dependent tuning of peptide-MHC molecular flexibility

Immunity. 2009 Dec 18;31(6):885-96. doi: 10.1016/j.immuni.2009.11.003.

Abstract

T cell-mediated immunity requires T cell receptor (TCR) cross-reactivity, the mechanisms behind which remain incompletely elucidated. The alphabeta TCR A6 recognizes both the Tax (LLFGYPVYV) and Tel1p (MLWGYLQYV) peptides presented by the human class I MHC molecule HLA-A2. Here we found that although the two ligands are ideal structural mimics, they form substantially different interfaces with A6, with conformational differences in the peptide, the TCR, and unexpectedly, the MHC molecule. The differences between the Tax and Tel1p ternary complexes could not be predicted from the free peptide-MHC structures and are inconsistent with a traditional induced-fit mechanism. Instead, the differences were attributable to peptide and MHC molecular motion present in Tel1p-HLA-A2 but absent in Tax-HLA-A2. Differential "tuning" of the dynamic properties of HLA-A2 by the Tax and Tel1p peptides thus facilitates cross-recognition and impacts how structural diversity can be presented to and accommodated by receptors of the immune system.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Antigen Presentation*
  • Cross Reactions
  • Crystallography, X-Ray
  • HLA-A2 Antigen / chemistry
  • HLA-A2 Antigen / immunology*
  • HLA-A2 Antigen / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / immunology*
  • Oligopeptides / chemistry
  • Oligopeptides / immunology
  • Protein Structure, Secondary
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / immunology*
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / immunology
  • Recombinant Proteins / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / immunology*
  • Thermodynamics

Substances

  • HLA-A2 Antigen
  • Intracellular Signaling Peptides and Proteins
  • Oligopeptides
  • Receptors, Antigen, T-Cell, alpha-beta
  • Recombinant Proteins
  • Saccharomyces cerevisiae Proteins
  • Protein-Serine-Threonine Kinases
  • TEL1 protein, S cerevisiae

Associated data

  • PDB/3H7B
  • PDB/3H9H
  • PDB/3H9S
  • PDB/3IXA