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

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 (TRAV4TRAJ21-TRBV28TRBJ2-3 and TRAV4 TRAJ8-TRBV9TRBJ2-1)， originating from a polyclonal T-cell repertoire， bind to HLA-B*07:02， presenting a 13-amino-acid-long tumour-associated peptide， NY-ESO-1. Comparison of the structures reveals that the two TCRs differentially binds NY-ESO-1-HLA-B*07:02 complex， and induces differing extent of conformational change of the NY-ESO-1 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.