title: Modification of MHC anchor residues generates heteroclitic peptides that alter TCR binding and T cell recognition.
abstract: Improving T cell Ags by altering MHC anchor residues is a common strategy used to enhance peptide vaccines, but there has been little assessment of how such modifications affect TCR binding and T cell recognition. In this study, we use surface plasmon resonance and peptide-MHC tetramer binding at the cell surface to demonstrate that changes in primary peptide anchor residues can substantially and unpredictably alter TCR binding. We also demonstrate that the ability of TCRs to differentiate between natural and anchor-modified heteroclitic peptides distinguishes T cells that exhibit a strong preference for either type of Ag. Furthermore, we show that anchor-modified heteroclitic peptides prime T cells with different TCRs compared with those primed with natural Ag. Thus, vaccination with heteroclitic peptides may elicit T cells that exhibit suboptimal recognition of the intended natural Ag and, consequently, impaired functional attributes in vivo. Heteroclitic peptide-based immune interventions therefore require careful evaluation to ensure efficacy in the clinic.
authors.affiliation: Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom.
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.forename: Emily S J
authors.initials: ES
authors.lastname: Edwards
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Wynn
authors.forename: Mathew
authors.initials: M
authors.lastname: Clement
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.forename: Julia
authors.initials: J
authors.lastname: Ekeruche
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Adams
authors.forename: Ania
authors.initials: A
authors.lastname: Skowera
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
mesh_terms: D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D009154:Mutation; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019151:Peptide Library; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C408902:MHC binding peptide; D009842:Oligopeptides; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell