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Proteasome-catalyzed peptide splicing represents an additional catalytic activity of proteasomes contributing to the pool of MHC-class I-presented epitopes. We here biochemically and functionally characterized a new melanoma gp100 derived spliced epitope. We demonstrate that the gp100(mel)47-52/40-42 antigenic peptide is generated in vitro and in cellulo by a not yet described proteasomal condensation reaction. gp100(mel)47-52/40-42 generation is enhanced in the presence of the β5i/LMP7 proteasome-subunit and elicits a peptide-specific CD8(+) T cell response. Importantly, we demonstrate that different gp100(mel)-derived spliced epitopes are generated and presented to CD8(+) T cells with efficacies comparable to non-spliced canonical tumor epitopes and that gp100(mel)-derived spliced epitopes trigger activation of CD8(+) T cells found in peripheral blood of half of the melanoma patients tested. Our data suggest that both transpeptidation and condensation reactions contribute to the frequent generation of spliced epitopes also in vivo and that their immune relevance may be comparable to non-spliced epitopes.

Original publication

DOI

10.1038/srep24032

Type

Journal article

Journal

Scientific reports

Publication Date

06/04/2016

Volume

6

Pages

24032 - 24032

Addresses

Institut für Biochemie, Charité-Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany.

Keywords

CD8-Positive T-Lymphocytes, Cell Line, Tumor, Hela Cells, Melanocytes, Humans, Melanoma, Proteasome Endopeptidase Complex, Peptides, Antigens, Antigens, Neoplasm, Epitopes, Epitopes, T-Lymphocyte, Probability, Case-Control Studies, Antigen Presentation, Alternative Splicing, Catalysis, Algorithms, Interferon-gamma, gp100 Melanoma Antigen