TCR-induced alteration of primary MHC peptide anchor residue.

Autor: Madura F; School of Medicine, Cardiff University, Cardiff, UK., Rizkallah PJ; School of Medicine, Cardiff University, Cardiff, UK., Legut M; School of Medicine, Cardiff University, Cardiff, UK., Holland CJ; School of Medicine, Cardiff University, Cardiff, UK.; Immunocore Ltd., Abingdon, UK., Fuller A; School of Medicine, Cardiff University, Cardiff, UK., Bulek A; School of Medicine, Cardiff University, Cardiff, UK., Schauenburg AJ; School of Medicine, Cardiff University, Cardiff, UK., Trimby A; School of Medicine, Cardiff University, Cardiff, UK., Hopkins JR; School of Medicine, Cardiff University, Cardiff, UK., Wells SA; Department of Chemical Engineering, University of Bath, Bath, UK., Godkin A; School of Medicine, Cardiff University, Cardiff, UK., Miles JJ; School of Medicine, Cardiff University, Cardiff, UK.; Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia., Sami M; Immunocore Ltd., Abingdon, UK., Li Y; Immunocore Ltd., Abingdon, UK., Liddy N; Immunocore Ltd., Abingdon, UK., Jakobsen BK; Immunocore Ltd., Abingdon, UK., Loveridge EJ; School of Chemistry, Cardiff University, Cardiff, UK.; Department of Chemistry, Swansea University, Swansea, UK., Cole DK; School of Medicine, Cardiff University, Cardiff, UK.; Immunocore Ltd., Abingdon, UK., Sewell AK; School of Medicine, Cardiff University, Cardiff, UK.; Systems Immunity Research Institute, Cardiff University, Cardiff, UK.
Jazyk: angličtina
Zdroj: European journal of immunology [Eur J Immunol] 2019 Jul; Vol. 49 (7), pp. 1052-1066. Date of Electronic Publication: 2019 May 27.
DOI: 10.1002/eji.201948085
Abstrakt: The HLA-A*02:01-restricted decapeptide EAAGIGILTV, derived from melanoma antigen recognized by T-cells-1 (MART-1) protein, represents one of the best-studied tumor associated T-cell epitopes, but clinical results targeting this peptide have been disappointing. This limitation may reflect the dominance of the nonapeptide, AAGIGILTV, at the melanoma cell surface. The decapeptide and nonapeptide are presented in distinct conformations by HLA-A*02:01 and TCRs from clinically relevant T-cell clones recognize the nonapeptide poorly. Here, we studied the MEL5 TCR that potently recognizes the nonapeptide. The structure of the MEL5-HLA-A*02:01-AAGIGILTV complex revealed an induced fit mechanism of antigen recognition involving altered peptide-MHC anchoring. This "flexing" at the TCR-peptide-MHC interface to accommodate the peptide antigen explains previously observed incongruences in this well-studied system and has important implications for future therapeutic approaches. Finally, this study expands upon the mechanisms by which molecular plasticity can influence antigen recognition by T cells.
(© 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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