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

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.

• Authors: 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 Tomkinson, Jacques Neefjes, Peter M Kloetzel, David W Rodgers, Louis B Hersh, Jan W Drijfhout, Peter A van Veelen, Ferry Ossendorp, Cornelis J M Melief
• Journal: Nature immunology (Nat Immunol) Vol. 12 Issue 1 Pg. 45-53 (Jan 2011) ISSN: 1529-2916 [Electronic] United States
• PMID: 21151101 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Epitopes, T-Lymphocyte
• HLA-A3 Antigen
• Peptide Fragments
• RNA, Small Interfering
• Metalloendopeptidases
• thimet oligopeptidase
• nardilysin
• Proteasome Endopeptidase Complex

Topics

• Antigen Presentation (genetics)
• Antigens, Neoplasm (chemistry, immunology, metabolism)
• Cytotoxicity, Immunologic (genetics)
• Epitopes, T-Lymphocyte (chemistry, immunology, metabolism)
• HLA-A3 Antigen (metabolism)
• Humans
• K562 Cells
• Metalloendopeptidases (genetics, immunology, metabolism)
• Peptide Fragments (chemistry, immunology, metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Binding
• RNA, Small Interfering (genetics)
• T-Lymphocytes, Cytotoxic (immunology, metabolism, pathology)
• Transgenes (genetics)