TY - JOUR
T1 - TCR-induced alteration of primary MHC peptide anchor residue
AU - Madura, Florian
AU - Rizkallah, Pierre J.
AU - Legut, Mateusz
AU - Holland, Christopher J.
AU - Fuller, Anna
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.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
KW - crystal structure
KW - MART-1/Melan-A
KW - peptide–major histocompatibility complex (pMHC)
KW - surface plasmon resonance (SPR)
KW - T cell: T-cell receptor (TCR)
UR - http://www.scopus.com/inward/record.url?scp=85068264205&partnerID=8YFLogxK
U2 - 10.1002/eji.201948085
DO - 10.1002/eji.201948085
M3 - Article
C2 - 31091334
AN - SCOPUS:85068264205
VL - 49
SP - 1052
EP - 1066
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 7
ER -