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Publication Abstract from PubMed

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, due to a specific increase in T-cell receptor (TCR) binding affinity for the cognate antigen. Structural analysis revealed the potential for new contacts between the MEL5 TCR 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.

T-Cell Receptor optimized peptide skewing of the T-cell repertoire can enhance antigen targeting.,Ekeruche-Makinde J, Clement M, Cole DK, Edwards ES, Ladell K, Miles JJ, Matthews KK, Fuller A, Lloyd KA, Madura F, Dolton GM, Pentier J, Lissina A, Gostick E, Baxter TK, Baker BM, Rizkallah PJ, Price DA, Wooldridge L, Sewell AK J Biol Chem. 2012 Sep 5. PMID:22952231^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.