title: T-cell receptors: tugging on the anchor for a tighter hold on the tumor-associated peptide.
abstract: Although it has been shown that human tumor-associated, HLA anchor residue modified "heteroclitic" peptides may induce stronger immune responses than wild-type peptides in cancer vaccine trials, it has also been shown that some T cells primed with these heteroclitic peptides subsequently fail to recognize the natural, tumor-expressed peptide efficiently. This may provide a molecular reason for why clinical trials of these peptides have been thus far unsuccessful. In this issue of the European Journal of Immunology, Madura et al. [Eur. J. Immunol. 2015. 45: 584-591] highlight a novel twist on T-cell receptor (TCR) recognition of HLA-peptide complexes. Tumor-associated peptides often lack canonical anchor residues, which can be substituted for the optimal residue to improve their antigenicity. T-cell cross-reactivity between the natural and modified (heteroclitic) peptides is essential for this approach to work and depends on whether the anchor residue substitution influences peptide conformation. The Melan-A/MART-126-35 peptide epitope is an example where T cells can make this distinction, with the natural peptide stimulating higher affinity CD8(+) T cells than the heteroclitic peptide, despite the heteroclitic peptide's more stable association with HLA-A2. The molecular basis for peptide discrimination is identified through the structure of the TCR bound to the natural peptide; TCR engagement of the natural peptide "lifts" its amino-terminus partly away from the HLA peptide binding groove, forming a higher affinity interface with the TCR than is formed with the anchor residue "optimized" heteroclitic peptide, which cannot be "pulled" from the HLA groove.
authors.affiliation: Section of Molecular Immunology, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Dyson
mesh_terms: D000409:Alanine / Q000737:chemistry*; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D015789:HLA-A2 Antigen / Q000737:chemistry*; D006801:Humans; D007930:Leucine / Q000737:chemistry*; D058965:MART-1 Antigen / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry*
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; D007930:Leucine; D000409:Alanine
keywords: Crystal structure; HLA-peptide complex; Melan-A/MART-1; T cell; TCR