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 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

doi:10.1038/ni.1974

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 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

Research output: Contribution to journal › Article › peer-review

94 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 language	English
Pages (from-to)	45-53
Number of pages	9
Journal	Nature Immunology
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/ni.1974
State	Published - 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.

Funding

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

Funders	Funder number
Dutch Cancer Society	UL 2005-3245
Stichting Vanderes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1038/ni.1974

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Kessler, J. H., Khan, S., Seifert, U., Le Gall, S., Chow, K. M., Paschen, A., Bres-Vloemans, S. A., De Ru, A., Van Montfoort, N., Franken, K. L. M. C., Benckhuijsen, W. E., Brooks, J. M., Van Hall, T., Ray, K., Mulder, A., Doxiadis, I. I. N., Van Swieten, P. F., Overkleeft, H. S., Prat, A., ... Melief, C. J. M. (2011). Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes. Nature Immunology, 12(1), 45-53. https://doi.org/10.1038/ni.1974

@article{326e7e1ca64d4fc1b66ec5006343b236,

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.",

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

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.",

year = "2011",

month = jan,

doi = "10.1038/ni.1974",

language = "English",

volume = "12",

pages = "45--53",

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Kessler, JH, Khan, S, Seifert, U, Le Gall, S, Chow, KM, Paschen, A, Bres-Vloemans, SA, De Ru, A, Van Montfoort, N, Franken, KLMC, Benckhuijsen, WE, Brooks, JM, Van Hall, T, Ray, K, Mulder, A, Doxiadis, IIN, Van Swieten, PF, Overkleeft, HS, Prat, A, Tomkinson, B, Neefjes, J, Kloetzel, PM, Rodgers, DW, Hersh, LB, Drijfhout, JW, Van Veelen, PA, Ossendorp, F & Melief, CJM 2011, 'Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes', Nature Immunology, vol. 12, no. 1, pp. 45-53. https://doi.org/10.1038/ni.1974

TY - JOUR

T1 - Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes

AU - Kessler, Jan H.

AU - Khan, Selina

AU - Seifert, Ulrike

AU - Le Gall, Sylvie

AU - Chow, K. Martin

AU - Paschen, Annette

AU - Bres-Vloemans, Sandra A.

AU - De Ru, Arnoud

AU - Van Montfoort, Nadine

AU - Franken, Kees L.M.C.

AU - Benckhuijsen, Willemien E.

AU - Brooks, Jill M.

AU - Van Hall, Thorbald

AU - Ray, Kallol

AU - Mulder, Arend

AU - Doxiadis, Ilias I.N.

AU - Van Swieten, Paul F.

AU - Overkleeft, Hermen S.

AU - Prat, Annik

AU - Tomkinson, Birgitta

AU - Neefjes, Jacques

AU - Kloetzel, Peter M.

AU - Rodgers, David W.

AU - Hersh, Louis B.

AU - Drijfhout, Jan W.

AU - Van Veelen, Peter A.

AU - Ossendorp, Ferry

AU - Melief, Cornelis J.M.

N1 - 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.

PY - 2011/1

Y1 - 2011/1

N2 - 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.

AB - 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.

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DO - 10.1038/ni.1974

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VL - 12

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JO - Nature Immunology

JF - Nature Immunology

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

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

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