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.
Kok Fei Chan  1  2  3  4 ,  Benjamin S Gully  3  5 ,  Stephanie Gras  3  5 ,  Dennis X Beringer  3 ,  Lars Kjer-Nielsen  2 ,  Jonathan Cebon  1 ,  James McCluskey  2 ,  Weisan Chen  6  7 ,  Jamie Rossjohn  8  9  10
Affiliations
  • 1. Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia.
  • 2. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, 3010, Australia.
  • 3. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
  • 4. Department of Biochemistry & Genetics, La Trobe Institute of Molecular Science, La Trobe University, Bundoora, VIC, 3086, Australia.
  • 5. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia.
  • 6. Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia. [email protected].
  • 7. Department of Biochemistry & Genetics, La Trobe Institute of Molecular Science, La Trobe University, Bundoora, VIC, 3086, Australia. [email protected].
  • 8. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia. [email protected].
  • 9. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia. [email protected].
  • 10. Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK. [email protected].
PMID: 29531227 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.