1. Divergent T-cell receptor recognition modes of a HLA-I restricted extended tumour-associated peptide.
- Author
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Chan KF, Gully BS, Gras S, Beringer DX, Kjer-Nielsen L, Cebon J, McCluskey J, Chen W, and Rossjohn J
- Subjects
- HLA-B7 Antigen chemistry, HLA-B7 Antigen genetics, Humans, Models, Molecular, Neoplasm Proteins chemistry, Neoplasm Proteins genetics, Neoplasms genetics, Peptides chemistry, Peptides genetics, Protein Binding, Receptors, Antigen, T-Cell chemistry, Receptors, Antigen, T-Cell genetics, HLA-B7 Antigen metabolism, Neoplasm Proteins metabolism, Neoplasms metabolism, Peptides metabolism, Receptors, Antigen, T-Cell metabolism
- 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.- Published
- 2018
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