TCR‐induced alteration of primary MHC peptide anchor residue

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.

T cell receptor interactions with human leukocyte antigen govern indirect peptide selectivity for the cancer testis antigen MAGE-A4

“…Site-directed mutagenesis together with structural and biophysical analysis revealed a novel mechanism of TCR-peptide selectivity whereby the CDR1α loop of the TCR could sense the chemical properties of peptide residue 1 via a molecular gateway guided by a conformational change in HLA-A*02:01 residue Trp-167. Consistent with other studies comparing natural and affinity-enhanced TCRs ( 25 , 37 , 47 – 51 ), this binding selectivity was conserved for both the GVY01 TCR and an affinity-enhanced TCR variant, demonstrating that the fine selectivity in this system was maintained by the engineered version of the TCR.…”

“…Importantly, the TCR-pHLA contact interface at Asp-4 and Arg-6 did not require major structural remodeling of A2-GVY ( Fig. 2 B ), as has been observed for other TCR-pHLA interactions ( 31 , 36 , 37 ).…”

Peptide Binding to HLA-E Molecules in Humans, Nonhuman Primates, and Mice Reveals Unique Binding Peptides but Remarkably Conserved Anchor Residues

“…Remarkably, Gag97, which was recognized by CD8 + T cells from RM vaccinated with a rhCMV vector carrying SIV Ags (15), or Med15, an immunogenic T cell epitope in the context of Qa-1 b (13), are low MHC-E binding epitopes. Plasticity in TCRpeptide-HLA interactions, as demonstrated in the context of melanoma Ag-specific T cells (52), might result in the context of HLA-E, in conformational changes after initial recognition and binding of TCR to a low binding HLA-E/peptide complex, leading to increased binding, complex stability, and productive TCR signaling. This mechanism might be particularly relevant in the context of peptides that bind HLA-E with a bulging out, less stable conformation (53).…”

The discriminatory power of the T cell receptor

“…ID 70 (105) The MEL5, MEL187.c5, DMF4, and DMF5 were studied that recognise the MART-1 antigen. Two overlapping peptides were used: nonapeptide MART-1 (27)(28)(29)(30)(31)(32)(33)(34)(35) and decapeptide MART-1 (26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”