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

Nature Immunology volume 3, pages 169–174 (2002)Cite this article

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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Figure 1: AEP cleaves after asparagine94 in MBP.
Figure 2: The minimal epitope for the Ob. 1A12 TCR spans residues 87–96 (PVVHFFKNIV).
Figure 3: Inhibition of AEP activity enhances presentation of the MBP(85–99) epitope.
Figure 4: Overexpression of AEP in Mel Juso cell lines inhibits presentation of MBP.
Figure 5: CD11c+ MHC class II+ thymic DCs express AEP.

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Acknowledgements

We thank G. Stockinger for the G8.8 antibody; D. Ni Li for anti-AEP antiserum; N. Morrice for peptide sequencing; and the Resource Centre, School of Life Sciences Dundee for help with thymus isolation. Supported by Wellcome Trust programme grants (to C. W. and D. C. W.). D. M. was supported by an European Union training grant.

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Authors and Affiliations

  1. Division of Cell Biology and Immunology, Wellcome Trust Biocentre, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK

    Bénédicte Manoury, Daniela Mazzeo & Colin Watts

  2. Department of Clinical Immunology, Aarhus University Hospital, Skejby Sygehus, DK-8200, Aarhus, Denmark

    Lars Fugger

  3. Department of Pathology & Microbiology, School of Medical Sciences University of Bristol, University Walk, Bristol, BS8 1TD, UK

    Nick Viner, Mary Ponsford, Heather Streeter, Graziella Mazza & David C. Wraith

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Manoury, B., Mazzeo, D., Fugger, L. et al. Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP. Nat Immunol 3, 169–174 (2002). https://doi.org/10.1038/ni754

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