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dc.contributor.authorNanaware, Padma P.
dc.contributor.authorJurewicz, Mollie M.
dc.contributor.authorLeszyk, John D.
dc.contributor.authorShaffer, Scott A.
dc.contributor.authorStern, Lawrence J.
dc.date2022-08-11T08:09:52.000
dc.date.accessioned2022-08-23T16:46:27Z
dc.date.available2022-08-23T16:46:27Z
dc.date.issued2018-12-20
dc.date.submitted2019-01-07
dc.identifier.citation<p>Mol Cell Proteomics. 2018 Dec 20. pii: mcp.RA118.000956. doi: 10.1074/mcp.RA118.000956. [Epub ahead of print] <a href="https://doi.org/10.1074/mcp.RA118.000956">Link to article on publisher's site</a></p>
dc.identifier.issn1535-9476 (Linking)
dc.identifier.doi10.1074/mcp.RA118.000956
dc.identifier.pmid30573663
dc.identifier.urihttp://hdl.handle.net/20.500.14038/40883
dc.description.abstractPresentation 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=30573663&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsPublished 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.
dc.subjectAbsolute quantification
dc.subjectImmunoaffinity
dc.subjectImmunology
dc.subjectLabel-free quantification
dc.subjectMass Spectrometry
dc.subjectPeptidomics
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemistry
dc.subjectCell Biology
dc.subjectCells
dc.subjectComputational Biology
dc.subjectGenomics
dc.subjectImmunity
dc.subjectImmunopathology
dc.subjectMolecular Biology
dc.titleHLA-DO modulates the diversity of the MHC-II self-peptidome
dc.typeAccepted Manuscript
dc.source.journaltitleMolecular and cellular proteomics : MCP
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=4698&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/3686
dc.identifier.contextkey13578942
refterms.dateFOA2022-08-23T16:46:27Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathoapubs/3686
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentProteomics and Mass Spectometry Facility
dc.contributor.departmentDepartment of Pathology


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