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

Jan H. Kessler, Selina Khan, Ulrike Seifert, Sylvie Le Gall, K. Martin Chow, Annette Paschen, Sandra A. Bres-Vloemans, Arnoud De Ru, Nadine Van Montfoort, Kees L.M.C. Franken, Willemien E. Benckhuijsen, Jill M. Brooks, Thorbald Van Hall, Kallol Ray, Arend Mulder, Ilias I.N. Doxiadis, Paul F. Van Swieten, Hermen S. Overkleeft, Annik Prat, Birgitta TomkinsonJacques Neefjes, Peter M. Kloetzel, David W. Rodgers, Louis B. Hersh, Jan W. Drijfhout, Peter A. Van Veelen, Ferry Ossendorp, Cornelis J.M. Melief

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

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)45-53
Number of pages9
JournalNature Immunology
Volume12
Issue number1
DOIs
StatePublished - Jan 2011

Bibliographical note

Funding Information:
We thank T. Dannenberg and K. Textoris-Taube for technical assistance. Supported by the Dutch Cancer Society (UL 2005-3245) and Stichting Vanderes.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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