TCR-induced alteration of primary MHC peptide anchor residue

Florian Madura, Pierre J. Rizkallah, Mateusz Legut, Christopher J. Holland, Anna Fuller, Anna Bulek, Andrea J. Schauenburg, Andrew Trimby, Jade R. Hopkins, Stephen A. Wells, Andrew Godkin, John J. Miles, Malkit Sami, Yi Li, Nathaniel Liddy, Bent K. Jakobsen, E. Joel Loveridge, David K. Cole, Andrew K. Sewell

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1052-1066
Number of pages15
JournalEuropean Journal of Immunology
Volume49
Issue number7
Early online date15 May 2019
DOIs
Publication statusPublished - 1 Jul 2019

Keywords

  • crystal structure
  • MART-1/Melan-A
  • peptide–major histocompatibility complex (pMHC)
  • surface plasmon resonance (SPR)
  • T cell: T-cell receptor (TCR)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Madura, F., Rizkallah, P. J., Legut, M., Holland, C. J., Fuller, A., Bulek, A., ... Sewell, A. K. (2019). TCR-induced alteration of primary MHC peptide anchor residue. European Journal of Immunology, 49(7), 1052-1066. https://doi.org/10.1002/eji.201948085

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. Joel; Cole, David K.; Sewell, Andrew K.

In: European Journal of Immunology, Vol. 49, No. 7, 01.07.2019, p. 1052-1066.

Research output: Contribution to journalArticle

Madura, F, Rizkallah, PJ, Legut, M, Holland, CJ, Fuller, A, Bulek, A, Schauenburg, AJ, Trimby, A, Hopkins, JR, Wells, SA, Godkin, A, Miles, JJ, Sami, M, Li, Y, Liddy, N, Jakobsen, BK, Loveridge, EJ, Cole, DK & Sewell, AK 2019, 'TCR-induced alteration of primary MHC peptide anchor residue', European Journal of Immunology, vol. 49, no. 7, pp. 1052-1066. https://doi.org/10.1002/eji.201948085
Madura F, Rizkallah PJ, Legut M, Holland CJ, Fuller A, Bulek A et al. TCR-induced alteration of primary MHC peptide anchor residue. European Journal of Immunology. 2019 Jul 1;49(7):1052-1066. https://doi.org/10.1002/eji.201948085
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. Joel ; Cole, David K. ; Sewell, Andrew K. / TCR-induced alteration of primary MHC peptide anchor residue. In: European Journal of Immunology. 2019 ; Vol. 49, No. 7. pp. 1052-1066.
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abstract = "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.",
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AU - Rizkallah, Pierre J.

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AU - Bulek, Anna

AU - Schauenburg, Andrea J.

AU - Trimby, Andrew

AU - Hopkins, Jade R.

AU - Wells, Stephen A.

AU - Godkin, Andrew

AU - Miles, John J.

AU - Sami, Malkit

AU - Li, Yi

AU - Liddy, Nathaniel

AU - Jakobsen, Bent K.

AU - Loveridge, E. Joel

AU - Cole, David K.

AU - Sewell, Andrew K.

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