Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide

Nat Commun. 2018 Mar 12;9(1):1026. doi: 10.1038/s41467-018-03321-w.

Abstract

Human leukocyte antigen (HLA)-I molecules generally bind short peptides (8-10 amino acids), although extended HLA-I restricted peptides (>10 amino acids) can be presented to T cells. However, the function of such extended HLA-I epitopes in tumour immunity, and how they would be recognised by T-cell receptors (TCR) remains unclear. Here we show that the structures of two distinct TCRs (TRAV4+TRAJ21+-TRBV28+TRBJ2-3+ and TRAV4 + TRAJ8+-TRBV9+TRBJ2-1+), originating from a polyclonal T-cell repertoire, bind to HLA-B*07:02, presenting a 13-amino-acid-long tumour-associated peptide, NY-ESO-160-72. Comparison of the structures reveals that the two TCRs differentially binds NY-ESO-160-72-HLA-B*07:02 complex, and induces differing extent of conformational change of the NY-ESO-160-72 epitope. Accordingly, polyclonal TCR usage towards an extended HLA-I restricted tumour epitope translates to differing TCR recognition modes, whereby extensive flexibility at the TCR-pHLA-I interface engenders recognition.

Publication types

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

MeSH terms

  • HLA-B7 Antigen / chemistry
  • HLA-B7 Antigen / genetics
  • HLA-B7 Antigen / metabolism*
  • Humans
  • Models, Molecular
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Peptides / chemistry
  • Peptides / genetics
  • Peptides / metabolism*
  • Protein Binding
  • Receptors, Antigen, T-Cell / chemistry
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*

Substances

  • HLA-B*07:02 antigen
  • HLA-B7 Antigen
  • Neoplasm Proteins
  • Peptides
  • Receptors, Antigen, T-Cell