Structural basis for ineffective T‐cell responses to MHC anchor residue‐improved “heteroclitic” peptides

• Published in: European journal of immunology Vol. 45; no. 2; pp. 584 - 591
• Main Authors: Madura, Florian, Rizkallah, Pierre J., Holland, Christopher J., Fuller, Anna, Bulek, Anna, Godkin, Andrew J., Schauenburg, Andrea J., Cole, David K., Sewell, Andrew K.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.02.2015; BlackWell Publishing Ltd
• Subjects: Alanine - chemistry; Alanine - genetics; Amino Acid Sequence; Amino Acid Substitution; Cross‐reactivity; Crystal structure; Crystallography, X-Ray; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Epitopes, T-Lymphocyte - metabolism; Escherichia coli - genetics; Escherichia coli - metabolism; Gene Expression; HLA-A2 Antigen - chemistry; HLA-A2 Antigen - genetics; HLA-A2 Antigen - immunology; Humans; Leucine - chemistry; Leucine - genetics; MART-1 Antigen - chemistry; MART-1 Antigen - genetics; MART-1 Antigen - immunology; MART‐1; Medical research; Melanoma; Melan‐A; Models, Molecular; Molecular Immunology; Molecular Sequence Data; Peptides; Peptides - chemistry; Peptides - genetics; Peptides - immunology; Peptide‐major histocompatibility complex; Protein Binding; Protein Interaction Domains and Motifs; Receptors, Antigen, T-Cell, alpha-beta - chemistry; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - immunology; Surface plasmon resonance; T cell receptors; T-Lymphocytes, Cytotoxic - cytology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; TCR; T‐cell; TCR; T-cell; MART-1; Cross-reactivity; Melanoma; Peptide-major histocompatibility complex; Surface plasmon resonance; Melan-A; Crystal structure
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.201445114

MHC anchor residue‐modified “heteroclitic” peptides have been used in many cancer vaccine trials and often induce greater immune responses than the wild‐type peptide. The best‐studied system to date is the decamer MART‐1/Melan‐A26–35 peptide, EAAGIGILTV, where the natural alanine at position 2 has been modified to leucine to improve human leukocyte antigen (HLA)‐A*0201 anchoring. The resulting ELAGIGILTV peptide has been used in many studies. We recently showed that T cells primed with the ELAGIGILTV peptide can fail to recognize the natural tumor‐expressed peptide efficiently, thereby providing a potential molecular reason for why clinical trials of this peptide have been unsuccessful. Here, we solved the structure of a TCR in complex with HLA‐A*0201‐EAAGIGILTV peptide and compared it with its heteroclitic counterpart , HLA‐A*0201‐ELAGIGILTV. The data demonstrate that a suboptimal anchor residue at position 2 enables the TCR to “pull” the peptide away from the MHC binding groove, facilitating extra contacts with both the peptide and MHC surface. These data explain how a TCR can distinguish between two epitopes that differ by only a single MHC anchor residue and demonstrate how weak MHC anchoring can enable an induced‐fit interaction with the TCR. Our findings constitute a novel demonstration of the extreme sensitivity of the TCR to minor alterations in peptide conformation.