Department of Pathology; Proteomics and Mass Spectometry Facility; Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Biochemistry | Cell Biology | Cells | Computational Biology | Genomics | Immunity | Immunopathology | Molecular Biology
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.
Absolute quantification, Immunoaffinity, Immunology, Label-free quantification, Mass Spectrometry, Peptidomics
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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.
DOI of Published Version
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
Molecular and cellular proteomics : MCP
Nanaware, Padma P.; Jurewicz, Mollie M.; Leszyk, John D.; Shaffer, Scott A.; and Stern, Lawrence J., "HLA-DO modulates the diversity of the MHC-II self-peptidome" (2018). Open Access Articles. 3686.
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