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T-cell Receptor-optimized Peptide Skewing of the T-cell Repertoire Can Enhance Antigen Targeting

DOI: 10.1074/jbc.M112.386409 DOI Help
PMID: 22952231 PMID Help

Authors: Julia Ekeruche-makinde (Cardiff University School of Medicine) , Mathew Clement (Cardiff University School of Medicine) , David K. Cole (Cardiff University School of Medicine) , Emily S. J. Edwards (Cardiff University School of Medicine) , Kristin Ladell (Cardiff University School of Medicine) , John J. Miles (Cardiff University School of Medicine) , Katherine K. Matthews (Cardiff University School of Medicine) , Anna Fuller (Cardiff University School of Medicine) , Katy A. Lloyd (Cardiff University School of Medicine) , Florian Madura (Cardiff University School of Medicine) , Garry M. Dolton (Cardiff University School of Medicine) , Johanne Pentier (Cardiff University School of Medicine) , Anna Lissina (Cardiff University School of Medicine) , Emma Gostick (Cardiff University School of Medicine) , Tiffany K. Baxter (Cardiff University School of Medicine) , Brian M. Baker (University of Notre Dame) , Pierre Rizkallah (Cardiff University School of Medicine) , David A. Price (Cardiff University School of Medicine) , Linda Wooldridge (Cardiff University School of Medicine) , Andrew K. Sewell (Cardiff University School of Medicine)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 287 (44) , PAGES 37269 - 37281

State: Published (Approved)
Published: October 2012

Open Access Open Access

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 A27–35 (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.

Journal Keywords: Amino; Antigen; Antigens; Neoplasm; CD8-Positive; Cancer; Cell; Tumor; Circular; HLA-A2; Humans; Kinetics; MART-1; Melanoma; Models; Molecular; Peptide; Protein; Secondary; Receptors; Antigen; T-Cell; Surface Plasmon Resonance

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography