T-cell receptor-optimized peptide skewing of the T-cell repertoire can enhance antigen targeting

Julia Ekeruche-Makinde, Mathew Clement, David K Cole, Emily S J Edwards, Kristin Ladell, John J Miles, Katherine K Matthews, Anna Fuller, Katy A Lloyd, Florian Madura, Garry M Dolton, Johanne Pentier, Anna Lissina, Emma Gostick, Tiffany K Baxter, Brian M Baker, Pierre J Rizkallah, David A Price, Linda Wooldridge, Andrew K Sewell

Research output: Contribution to journalArticle (Academic Journal)peer-review

29 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)37269-81
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number44
DOIs
Publication statusPublished - 26 Oct 2012

Keywords

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Antigen Presentation
  • Antigens, Neoplasm
  • CD8-Positive T-Lymphocytes
  • Cancer Vaccines
  • Cell Line, Tumor
  • Circular Dichroism
  • HLA-A2 Antigen
  • Humans
  • Kinetics
  • MART-1 Antigen
  • Melanoma
  • Models, Molecular
  • Peptide Fragments
  • Protein Binding
  • Protein Structure, Secondary
  • Receptors, Antigen, T-Cell
  • Surface Plasmon Resonance

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