title: Divergent paths for the selection of immunodominant epitopes from distinct antigenic sources.
abstract: Immunodominant epitopes are few selected epitopes from complex antigens that initiate T-cell responses. Here to provide further insights into this process, we use a reductionist cell-free antigen-processing system composed of defined components. We use the system to characterize steps in antigen processing of pathogen-derived proteins or autoantigens and we find distinct paths for peptide processing and selection. Autoantigen-derived immunodominant epitopes are resistant to digestion by cathepsins, whereas pathogen-derived epitopes are sensitive. Sensitivity to cathepsins enforces capture of pathogen-derived epitopes by major histocompatibility complex class II (MHC class II) before processing, and resistance to HLA-DM-mediated-dissociation preserves the longevity of those epitopes. We show that immunodominance is established by higher relative abundance of the selected epitopes, which survive cathepsin digestion either by binding to MHC class II and resisting DM-mediated-dissociation, or being chemically resistant to cathepsins degradation. Non-dominant epitopes are sensitive to both DM and cathepsins and are destroyed.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: AeRyon
authors.initials: A
authors.lastname: Kim
authors.affiliation: The Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Isamu Z
authors.initials: IZ
authors.lastname: Hartman
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Poore
authors.affiliation: Department of Biological Chemistry, Mass Spectrometry and Proteomics Facility, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Boronina
authors.affiliation: Department of Biological Chemistry, Mass Spectrometry and Proteomics Facility, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Cole
authors.affiliation: The Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Nianbin
authors.initials: N
authors.lastname: Song
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Laboratori d'Immunologia Cellular, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Ciudad
authors.affiliation: Laboratory of Immunology, National Eye Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Caspi
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Laboratori d'Immunologia Cellular, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Jaraquemada
authors.affiliation: 1] Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] The Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Scheherazade
authors.initials: S
authors.lastname: Sadegh-Nasseri
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D002403:Cathepsins / Q000737:chemistry; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000821:virology; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology*; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D001324:Autoantigens; D000949:Histocompatibility Antigens Class II; D016056:Immunodominant Epitopes; D014764:Viral Proteins; D002403:Cathepsins