Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP

Bénédicte Manoury; Daniela Mazzeo; Lars Fugger; Nick Viner; Mary Ponsford; Heather Streeter; Graziella Mazza; David C Wraith; Colin Watts

doi:10.1038/ni754

Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP

Bénédicte Manoury, Daniela Mazzeo, Lars Fugger, Nick Viner, Mary Ponsford, Heather Streeter, Graziella Mazza, David C Wraith, Colin Watts

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

167 Citations (Scopus)

Abstract

Little is known about the processing of putative human autoantigens and why tolerance is established to some T cell epitopes but not others. Here we show that a principal human HLA-DR2-restricted epitope--amino acids 85-99 of myelin basic protein, MBP(85-99)--contains a processing site for the cysteine protease asparagine endopeptidase (AEP). Presentation of this epitope by human antigen-presenting cells is inversely proportional to the amount of cellular AEP activity: inhibition of AEP in living cells greatly enhances presentation of the MBP(85-99) epitope, whereas overexpression of AEP diminishes presentation. These results indicate that central tolerance to this encephalitogenic MBP epitope may not be established because destructive processing limits its display in the thymus. Consistent with this hypothesis, AEP is expressed abundantly in thymic antigen-presenting cells.

Original language	English
Pages (from-to)	169-74
Number of pages	6
Journal	Nature Immunology
Volume	3
Issue number	2
DOIs	https://doi.org/10.1038/ni754
Publication status	Published - Feb 2002

Keywords

Amino Acid Sequence
Animals
Antigen Presentation
Cysteine Endopeptidases/metabolism
HLA-DR2 Antigen/immunology
Humans
Immunodominant Epitopes/immunology
Methaqualone
Mice
Mice, Inbred BALB C
Molecular Sequence Data
Myelin Basic Protein/immunology
Peptide Fragments/immunology
Thymus Gland/enzymology

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title = "Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP",

abstract = "Little is known about the processing of putative human autoantigens and why tolerance is established to some T cell epitopes but not others. Here we show that a principal human HLA-DR2-restricted epitope--amino acids 85-99 of myelin basic protein, MBP(85-99)--contains a processing site for the cysteine protease asparagine endopeptidase (AEP). Presentation of this epitope by human antigen-presenting cells is inversely proportional to the amount of cellular AEP activity: inhibition of AEP in living cells greatly enhances presentation of the MBP(85-99) epitope, whereas overexpression of AEP diminishes presentation. These results indicate that central tolerance to this encephalitogenic MBP epitope may not be established because destructive processing limits its display in the thymus. Consistent with this hypothesis, AEP is expressed abundantly in thymic antigen-presenting cells.",

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author = "B{\'e}n{\'e}dicte Manoury and Daniela Mazzeo and Lars Fugger and Nick Viner and Mary Ponsford and Heather Streeter and Graziella Mazza and Wraith, {David C} and Colin Watts",

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AU - Manoury, Bénédicte

AU - Mazzeo, Daniela

AU - Fugger, Lars

AU - Viner, Nick

AU - Ponsford, Mary

AU - Streeter, Heather

AU - Mazza, Graziella

AU - Wraith, David C

AU - Watts, Colin

PY - 2002/2

Y1 - 2002/2

N2 - Little is known about the processing of putative human autoantigens and why tolerance is established to some T cell epitopes but not others. Here we show that a principal human HLA-DR2-restricted epitope--amino acids 85-99 of myelin basic protein, MBP(85-99)--contains a processing site for the cysteine protease asparagine endopeptidase (AEP). Presentation of this epitope by human antigen-presenting cells is inversely proportional to the amount of cellular AEP activity: inhibition of AEP in living cells greatly enhances presentation of the MBP(85-99) epitope, whereas overexpression of AEP diminishes presentation. These results indicate that central tolerance to this encephalitogenic MBP epitope may not be established because destructive processing limits its display in the thymus. Consistent with this hypothesis, AEP is expressed abundantly in thymic antigen-presenting cells.

AB - Little is known about the processing of putative human autoantigens and why tolerance is established to some T cell epitopes but not others. Here we show that a principal human HLA-DR2-restricted epitope--amino acids 85-99 of myelin basic protein, MBP(85-99)--contains a processing site for the cysteine protease asparagine endopeptidase (AEP). Presentation of this epitope by human antigen-presenting cells is inversely proportional to the amount of cellular AEP activity: inhibition of AEP in living cells greatly enhances presentation of the MBP(85-99) epitope, whereas overexpression of AEP diminishes presentation. These results indicate that central tolerance to this encephalitogenic MBP epitope may not be established because destructive processing limits its display in the thymus. Consistent with this hypothesis, AEP is expressed abundantly in thymic antigen-presenting cells.

KW - Amino Acid Sequence

KW - Animals

KW - Antigen Presentation

KW - Cysteine Endopeptidases/metabolism

KW - HLA-DR2 Antigen/immunology

KW - Humans

KW - Immunodominant Epitopes/immunology

KW - Methaqualone

KW - Mice

KW - Mice, Inbred BALB C

KW - Molecular Sequence Data

KW - Myelin Basic Protein/immunology

KW - Peptide Fragments/immunology

KW - Thymus Gland/enzymology

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DO - 10.1038/ni754

M3 - Article

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SN - 1529-2908

VL - 3

SP - 169

EP - 174

JO - Nature Immunology

JF - Nature Immunology

IS - 2

ER -

Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP

Abstract

Keywords

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