Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes

JH Kessler, S Khan, U Seifert, S Le Gall, KM Chow, A Paschen, SA Bres-Vloemans, A de Ru, N van Montfoort, KLMC Franken, WE Benckhuijsen, Jill Brooks, T van Hall, K Ray, A Mulder, IIN Doxiadis, PF van Swieten, HS Overkleeft, A Prat, B TomkinsonJ Neefjes, PM Kloetzel, DW Rodgers, LB Hersh, JW Drijfhout, PA van Veelen, F Ossendorp, CJM Melief

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Cytotoxic T lymphocytes (CTLs) recognize peptides presented by HLA class I molecules on the cell surface. The C terminus of these CTL epitopes is considered to be produced by the proteasome. Here we demonstrate that the cytosolic endopeptidases nardilysin and thimet oligopeptidase (TOP) complemented proteasome activity. Nardilysin and TOP were required, either together or alone, for the generation of a tumor-specific CTL epitope from PRAME, an immunodominant CTL epitope from Epstein-Barr virus protein EBNA3C, and a clinically important epitope from the melanoma protein MART-1. TOP functioned as C-terminal trimming peptidase in antigen processing, and nardilysin contributed to both the C-terminal and N-terminal generation of CTL epitopes. By broadening the antigenic peptide repertoire, nardilysin and TOP strengthen the immune defense against intracellular pathogens and cancer.
Original languageEnglish
Pages (from-to)45-U67
JournalNature Immunology
Issue number1
Publication statusPublished - 1 Jan 2011


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