UMMS Affiliation
Department of Pathology; Proteomics and Mass Spectometry Facility; Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences
Publication Date
2018-12-20
Document Type
Article Postprint
Disciplines
Amino Acids, Peptides, and Proteins | Biochemistry | Cell Biology | Cells | Computational Biology | Genomics | Immunity | Immunopathology | Molecular Biology
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.
Keywords
Absolute quantification, Immunoaffinity, Immunology, Label-free quantification, Mass Spectrometry, Peptidomics
Rights and Permissions
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
10.1074/mcp.RA118.000956
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
Journal/Book/Conference Title
Molecular and cellular proteomics : MCP
Related Resources
PubMed ID
30573663
Repository Citation
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.
https://escholarship.umassmed.edu/oapubs/3686
Included in
Amino Acids, Peptides, and Proteins Commons, Biochemistry Commons, Cell Biology Commons, Cells Commons, Computational Biology Commons, Genomics Commons, Immunity Commons, Immunopathology Commons, Molecular Biology Commons