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

JH Kessler; S Khan; U Seifert; S Le Gall; KM Chow; A Paschen; SA Bres-Vloemans; A de Ru; N van Montfoort; KLMC Franken; WE Benckhuijsen; Jill Brooks; T van Hall; K Ray; A Mulder; IIN Doxiadis; PF van Swieten; HS Overkleeft; A Prat; B Tomkinson; J Neefjes; PM Kloetzel; DW Rodgers; LB Hersh; JW Drijfhout; PA van Veelen; F Ossendorp; CJM Melief

doi:10.1038/ni.1974

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

JH Kessler, S Khan, U Seifert, S Le Gall, KM Chow, A Paschen, SA Bres-Vloemans, A de Ru, N van Montfoort, KLMC Franken, WE Benckhuijsen, Jill Brooks, T van Hall, K Ray, A Mulder, IIN Doxiadis, PF van Swieten, HS Overkleeft, A Prat, B TomkinsonJ Neefjes, PM Kloetzel, DW Rodgers, LB Hersh, JW Drijfhout, PA van Veelen, F Ossendorp, CJM Melief

Cancer and Genomic Sciences

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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-U67
Journal	Nature Immunology
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/ni.1974
Publication status	Published - 1 Jan 2011

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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, J., van Hall, T., Ray, K., Mulder, A., Doxiadis, IIN., van Swieten, PF., Overkleeft, HS., Prat, A., ... Melief, CJM. (2011). Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes. Nature Immunology, 12(1), 45-U67. https://doi.org/10.1038/ni.1974

@article{8edb4b4c185b4912855c0d5b26b41ae3,

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 = "JH Kessler and S Khan and U Seifert and {Le Gall}, S and KM Chow and A Paschen and SA Bres-Vloemans and {de Ru}, A and {van Montfoort}, N and KLMC Franken and WE Benckhuijsen and Jill Brooks and {van Hall}, T and K Ray and A Mulder and IIN Doxiadis and {van Swieten}, PF and HS Overkleeft and A Prat and B Tomkinson and J Neefjes and PM Kloetzel and DW Rodgers and LB Hersh and JW Drijfhout and {van Veelen}, PA and F Ossendorp and CJM Melief",

year = "2011",

month = jan,

day = "1",

doi = "10.1038/ni.1974",

language = "English",

volume = "12",

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journal = "Nature Immunology",

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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, J, 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-U67. https://doi.org/10.1038/ni.1974

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AU - Kessler, JH

AU - Khan, S

AU - Seifert, U

AU - Le Gall, S

AU - Chow, KM

AU - Paschen, A

AU - Bres-Vloemans, SA

AU - de Ru, A

AU - van Montfoort, N

AU - Franken, KLMC

AU - Benckhuijsen, WE

AU - Brooks, Jill

AU - van Hall, T

AU - Ray, K

AU - Mulder, A

AU - Doxiadis, IIN

AU - van Swieten, PF

AU - Overkleeft, HS

AU - Prat, A

AU - Tomkinson, B

AU - Neefjes, J

AU - Kloetzel, PM

AU - Rodgers, DW

AU - Hersh, LB

AU - Drijfhout, JW

AU - van Veelen, PA

AU - Ossendorp, F

AU - Melief, CJM

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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.

U2 - 10.1038/ni.1974

DO - 10.1038/ni.1974

M3 - Article

SN - 1529-2916

VL - 12

SP - 45-U67

JO - Nature Immunology

JF - Nature Immunology

IS - 1

ER -

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

Abstract

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