title: T-cell receptor-optimized peptide skewing of the T-cell repertoire can enhance antigen targeting.
abstract: Altered peptide antigens that enhance T-cell immunogenicity have been used to improve peptide-based vaccination for a range of diseases. Although this strategy can prime T-cell responses of greater magnitude, the efficacy of constituent T-cell clonotypes within the primed population can be poor. To overcome this limitation, we isolated a CD8(+) T-cell clone (MEL5) with an enhanced ability to recognize the HLA A*0201-Melan A(27-35) (HLA A*0201-AAGIGILTV) antigen expressed on the surface of malignant melanoma cells. We used combinatorial peptide library screening to design an optimal peptide sequence that enhanced functional activation of the MEL5 clone, but not other CD8(+) T-cell clones that recognized HLA A*0201-AAGIGILTV poorly. Structural analysis revealed the potential for new contacts between the MEL5 T-cell receptor and the optimized peptide. Furthermore, the optimized peptide was able to prime CD8(+) T-cell populations in peripheral blood mononuclear cell isolates from multiple HLA A*0201(+) individuals that were capable of efficient HLA A*0201(+) melanoma cell destruction. This proof-of-concept study demonstrates that it is possible to design altered peptide antigens for the selection of superior T-cell clonotypes with enhanced antigen recognition properties.
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, Wales, United Kingdom.
authors.forename: Julia
authors.initials: J
authors.lastname: Ekeruche-Makinde
authors.forename: Mathew
authors.initials: M
authors.lastname: Clement
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.forename: Emily S J
authors.initials: ES
authors.lastname: Edwards
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthews
authors.forename: Anna
authors.initials: A
authors.lastname: Fuller
authors.forename: Katy A
authors.initials: KA
authors.lastname: Lloyd
authors.forename: Florian
authors.initials: F
authors.lastname: Madura
authors.forename: Garry M
authors.initials: GM
authors.lastname: Dolton
authors.forename: Johanne
authors.initials: J
authors.lastname: Pentier
authors.forename: Anna
authors.initials: A
authors.lastname: Lissina
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: Tiffany K
authors.initials: TK
authors.lastname: Baxter
authors.forename: Brian M
authors.initials: BM
authors.lastname: Baker
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Rizkallah
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D015789:HLA-A2 Antigen / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D058965:MART-1 Antigen / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020349:Surface Plasmon Resonance
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell