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

Kok Fei Chan, Benjamin S. Gully, Stephanie Gras, Dennis X. Beringer, Lars Kjer-Nielsen, Jonathan Cebon, James McCluskey, Weisan Chen, Jamie Rossjohn

Research output: Contribution to journalArticleResearchpeer-review

39 Citations (Scopus)

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.

Original languageEnglish
Article number1026
Number of pages13
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

Keywords

  • adaptive immunity
  • antigen processing and presentation
  • tumour immunology
  • x-ray crystallography
  • ARC Centre of Excellence in Advanced Molecular Imaging

    Whisstock, J. (Primary Chief Investigator (PCI)), Abbey, B. (Chief Investigator (CI)), Nugent, K. A. (Chief Investigator (CI)), Quiney, H. M. (Chief Investigator (CI)), Godfrey, D. I. (Chief Investigator (CI)), Heath, W. (Chief Investigator (CI)), Fairlie, D. P. (Chief Investigator (CI)), Chapman, H. (Partner Investigator (PI)), Peele, A. (Partner Investigator (PI)), Davey, J. (Partner Investigator (PI)) & Wittmann, A. (Project Manager)

    30/06/1431/03/21

    Project: Research

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