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

Jan J.H. Kessler (1) , Selina S. Khan (1) , Ulrike Seifert (1) , Sylvie Le Gall (1) , K. Martin Chow (1) , Annette Paschen (1) , Sandra Bres-Vloemans (1) , Arnoud de Ru (1) , Nadine N. van Montfoort (1) , Kees Franken (1) , Willemien Benckhuijsen (1) , Jill Brooks (1) , Thorbald van Hall (1) , Kallol Ray (1) , Arend Mulder (1) , Ilias Doxiadis (1) , Paul van Swieten (1) , Hermen Overkleeft (1) , Annik Prat (1) , Brigitta Tomkinson (1) , Jacques J Neefjes (1) , Peter-M. M Kloetzel (1) , David Rodgers (1) , Louis Hersh (1) , Jan Wouter Drijfhout (1) , Peter van Veelen (1) , Ferry F.A. Ossendorp (1) , Cornelis J.M. Melief (1)

1 Dept. of Immunohematology and Blood Transfusion

Cytoxic T lymphocytes (CTLs) recognize peptides presented by HLA class I molecules on the cell surface. The C-terminus of these CTL epitopes is predominantly generated 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, and a clinically important epitope from melanoma-protein MART-1. TOP functioned as C-terminal trimming peptidase in antigen processing and nardilysin contributed to both C-terminal and N-terminal CTL epitope generation. By broadening the antigenic peptide repertoire, nardilysin and TOP strengthen the immune defense against intracellular pathogens and cancer.

Mots clés: Antigen presentation; Antigen processing; T cells; MHC; proteolysis; proteases

Jan J.H. Kessler, Selina S. Khan, Ulrike Seifert, Sylvie Le Gall, K. Martin Chow, et al.. Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes. Nature Immunology, 2010, ⟨10.1038/ni.1974⟩. ⟨hal-00599968⟩