title: Structural basis for ineffective T-cell responses to MHC anchor residue-improved "heteroclitic" peptides.
abstract: 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.
authors.affiliation: Division of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.
authors.forename: Florian
authors.initials: F
authors.lastname: Madura
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Rizkallah
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Holland
authors.forename: Anna
authors.initials: A
authors.lastname: Fuller
authors.forename: Anna
authors.initials: A
authors.lastname: Bulek
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Godkin
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Schauenburg
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
mesh_terms: D000409:Alanine / Q000737:chemistry* / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015789:HLA-A2 Antigen / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007930:Leucine / Q000737:chemistry* / Q000235:genetics; D058965:MART-1 Antigen / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins; D007930:Leucine; D000409:Alanine
keywords: Cross-reactivity; Crystal structure; MART-1; Melan-A; Melanoma; Peptide-major histocompatibility complex; Surface plasmon resonance; T-cell; TCR