Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP.
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.
Manoury
Bénédicte
B
Division of Cell Biology and Immunology, Wellcome Trust Biocentre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Mazzeo
Daniela
D
Fugger
Lars
L
Viner
Nick
N
Ponsford
Mary
M
Streeter
Heather
H
Mazza
Graziella
G
Wraith
David C
DC
Watts
Colin
C
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015802:HLA-DR2 Antigen / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D008702:Methaqualone; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000201:enzymology / Q000276:immunology
D015802:HLA-DR2 Antigen; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C107908:myelin basic protein 85-99; D008702:Methaqualone; D003546:Cysteine Endopeptidases; C447421:asparaginyl endopeptidase, lysosomal