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

JH Kessler, S Khan, U Seifert, S Le Gall, KM Chow… - Nature …, 2011 - nature.com
JH Kessler, S Khan, U Seifert, S Le Gall, KM Chow, A Paschen, SA Bres-Vloemans, A De Ru…
Nature immunology, 2011nature.com
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 …
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.
nature.com