TCR-induced alteration of primary MHC peptide anchor residue

Madura, Florian, Rizkallah, Pierre J., Legut, Mateusz, Holland, Christopher J., Fuller, Anna, Bulek, Anna, Schauenburg, Andrea J., Trimby, Andrew, Hopkins, Jade R., Wells, Stephen A., Godkin, Andrew, Miles, John J., Sami, Malkit, Li, Yi, Liddy, Nathaniel, Jakobsen, Bent K., Loveridge, E., Cole, David K., and Sewell, Andrew K. (2019) TCR-induced alteration of primary MHC peptide anchor residue. European Journal of Immunology, 49 (7). pp. 1052-1066.

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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.

Item ID: 60086
Item Type: Article (Research - C1)
ISSN: 1521-4141
Keywords: crystal structure, MART-1, Melan-A, peptide-major histocompatibility complex (pMHC), surface plasmon resonance (SPR), T cell, T-cell receptor (TCR)
Copyright Information: (C) 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Funders: Wellcome Trust (WT), UK Biotechnology and Biological Science Research Council (BBSRC), European Research Council (ERC)
Projects and Grants: WT086716MA, WT095767, CCSRC Grant BB/H001085, ERC 648283
Date Deposited: 31 Jul 2019 07:46
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320499 Immunology not elsewhere classified @ 100%
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