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

Ekeruche-Makinde, Julia, Clement, Mathew, Cole, David K., Edwards, Emily S.J., Ladell, Kristin, Miles, John, Matthews, Katherine K., Fuller, Anna, Lloyd, Katy A., Madura, Florian, Dolton, Garry M., Pentier, Johanne, Lissina, Anna, Gostick, Emma, Baxter, Tiffany K., Baker, Brian M., Rizkallah, Pierre J., Price, David A., Wooldridge, Linda, and Sewell, Andrew K. (2012) T-cell receptor-optimized peptide skewing of the T-cell repertoire can enhance antigen targeting. Journal of Biological Chemistry, 287 (44). pp. 37269-37281.

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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.

Item ID: 45182
Item Type: Article (Refereed Research - C1)
Keywords: immunology, immunotherapy, major histocompatibility complex (MHC), T-cell receptor, vaccine development
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ISSN: 1083-351X
Funders: Biotechnology and Biological Sciences Research Council (BBSRC), Wellcome Trust (WT), National Institutes of Health (NIH), Research Councils UK (RCUK), Wales Office of Research and Development (WORD), Medical Research Council (MRC)
Projects and Grants: BBSRC Grant BB/H001085/1, WT Grant WT086716, WT Grant WT095767, WT Grant WT079848MA, NIH Grant GM067079
Date Deposited: 16 Aug 2016 05:13
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110702 Applied Immunology (incl Antibody Engineering, Xenotransplantation and T-cell Therapies) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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