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 () and Jamie Rossjohn ()
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Kok Fei Chan: La Trobe University
Benjamin S. Gully: Monash University
Stephanie Gras: Monash University
Dennis X. Beringer: Monash University
Lars Kjer-Nielsen: The University of Melbourne
Jonathan Cebon: La Trobe University
James McCluskey: The University of Melbourne
Weisan Chen: La Trobe University
Jamie Rossjohn: Monash University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03321-w

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