title: 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.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. j.h.kessler@amc.uva.nl
authors.forename: Jan H
authors.initials: JH
authors.lastname: Kessler
authors.forename: Selina
authors.initials: S
authors.lastname: Khan
authors.forename: Ulrike
authors.initials: U
authors.lastname: Seifert
authors.forename: Sylvie
authors.initials: S
authors.lastname: Le Gall
authors.forename: K Martin
authors.initials: KM
authors.lastname: Chow
authors.forename: Annette
authors.initials: A
authors.lastname: Paschen
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Bres-Vloemans
authors.forename: Arnoud
authors.initials: A
authors.lastname: de Ru
authors.forename: Nadine
authors.initials: N
authors.lastname: van Montfoort
authors.forename: Kees L M C
authors.initials: KL
authors.lastname: Franken
authors.forename: Willemien E
authors.initials: WE
authors.lastname: Benckhuijsen
authors.forename: Jill M
authors.initials: JM
authors.lastname: Brooks
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
authors.forename: Kallol
authors.initials: K
authors.lastname: Ray
authors.forename: Arend
authors.initials: A
authors.lastname: Mulder
authors.forename: Ilias I N
authors.initials: II
authors.lastname: Doxiadis
authors.forename: Paul F
authors.initials: PF
authors.lastname: van Swieten
authors.forename: Hermen S
authors.initials: HS
authors.lastname: Overkleeft
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
authors.forename: Birgitta
authors.initials: B
authors.lastname: Tomkinson
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kloetzel
authors.forename: David W
authors.initials: DW
authors.lastname: Rodgers
authors.forename: Louis B
authors.initials: LB
authors.lastname: Hersh
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.forename: Ferry
authors.initials: F
authors.lastname: Ossendorp
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
mesh_terms: D017951:Antigen Presentation / Q000235:genetics; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D015791:HLA-A3 Antigen / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008666:Metalloendopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019076:Transgenes / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015791:HLA-A3 Antigen; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase; C087976:nardilysin; D046988:Proteasome Endopeptidase Complex