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    HLA-DO modulates the diversity of the MHC-II self-peptidome

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    Authors
    Nanaware, Padma P.
    Jurewicz, Mollie M.
    Leszyk, John D.
    Shaffer, Scott A.
    Stern, Lawrence J.
    UMass Chan Affiliations
    Graduate School of Biomedical Sciences
    Department of Biochemistry and Molecular Pharmacology
    Proteomics and Mass Spectometry Facility
    Department of Pathology
    Document Type
    Accepted Manuscript
    Publication Date
    2018-12-20
    Keywords
    Absolute quantification
    Immunoaffinity
    Immunology
    Label-free quantification
    Mass Spectrometry
    Peptidomics
    Amino Acids, Peptides, and Proteins
    Biochemistry
    Cell Biology
    Cells
    Computational Biology
    Genomics
    Immunity
    Immunopathology
    Molecular Biology
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    Abstract
    Presentation of antigenic peptides on MHC-II molecules is essential for tolerance to self and for initiation of immune responses against foreign antigens. DO (HLA-DO in humans, H2-O in mice) is a non-classical MHC-II protein that has been implicated in control of autoimmunity and regulation of neutralizing antibody responses to viruses. These effects likely are related to a role of DO in selecting MHC-II epitopes, but previous studies examining the effect of DO on presentation of selected CD4 T cell epitopes have been contradictory. To understand how DO modulates MHC-II antigen presentation, we characterized the full spectrum of peptides presented by MHC-II molecules expressed by DO-sufficient and DO-deficient antigen-presenting cells in vivo and in vitro using quantitative mass spectrometry approaches. We found that DO controlled the diversity of the presented peptide repertoire, with a subset of peptides presented only when DO was expressed. Antigen-presenting cells express another non-classical MHC-II protein, DM, which acts as a peptide editor by preferentially catalyzing the exchange of less stable MHC-II peptide complexes, and which is inhibited when bound to DO. Peptides presented uniquely in the presence of DO were sensitive to DM-mediated exchange, suggesting that decreased DM editing was responsible for the increased diversity. DO-deficient mice mounted CD4 T cell responses against wild-type antigen-presenting cells, but not vice versa, indicating that DO-dependent alterations in the MHC-II peptidome could be recognized by circulating T cells. These data suggest that cell-specific and regulated expression of HLA-DO serves to fine-tune MHC-II peptidomes, to enhance self-tolerance to a wide spectrum of epitopes while allowing focused presentation of immunodominant epitopes during an immune response.
    Source

    Mol Cell Proteomics. 2018 Dec 20. pii: mcp.RA118.000956. doi: 10.1074/mcp.RA118.000956. [Epub ahead of print] Link to article on publisher's site

    DOI
    10.1074/mcp.RA118.000956
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/40883
    PubMed ID
    30573663
    Related Resources

    Link to Article in PubMed

    Rights
    Published under license by The American Society for Biochemistry and Molecular Biology, Inc. Accepted manuscript posted as allowed by the publisher's copyright policy at http://www.mcponline.org/content/editorial-policies-and-practices#copyright.
    ae974a485f413a2113503eed53cd6c53
    10.1074/mcp.RA118.000956
    Scopus Count
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    Morningside Graduate School of Biomedical Sciences Scholarly Publications
    UMass Chan Faculty and Researcher Publications

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