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-1_60-72. Comparison of the structures reveals that the two TCRs differentially binds NY-ESO-1_60-72-HLA-B*07:02 complex, and induces differing extent of conformational change of the NY-ESO-1_60-72 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.

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