title: The cross-priming capacity and direct presentation potential of an autoantigen are separable and inversely related properties.
abstract: We investigated whether a prevalent epitope of the β-cell-specific autoantigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP206-214) reaches regional Ag-presentation pathways via unprocessed polypeptide chains, as free IGRP206-214 peptide or via preformed IGRP206-214/K(d) complexes. This was accomplished by expressing bacterial artificial chromosome transgenes encoding wild-type (stable) or ubiquitinated (unstable) forms of IGRP in IGRP-deficient NOD mice carrying MHC class I-deficient β-cells, dendritic cells, or B cells. We investigated the ability of the pancreatic lymph nodes of these mice to prime naive IGRP206-214-reactive CD8(+) T cells in vivo, either in response to spontaneous Ag shedding, or to synchronized forms of β-cell necrosis or apoptosis. When IGRP was made unstable by targeting it for proteasomal degradation within β-cells, the cross-priming, autoimmune-initiating potential of this autoantigen (designated autoantigenicity) was impaired. Yet at the same time, the direct presentation, CTL-targeting potential of IGRP (designated pathogenicity) was enhanced. The appearance of IGRP206-214 in regional Ag-presentation pathways was dissociated from transfer of IGRP206-214 or IGRP206-214/K(d) from β cells to dendritic cells. These results indicate that autoantigenicity and pathogenicity are separable and inversely related properties and suggest that pathogenic autoantigens, capable of efficiently priming CTLs while marking target cells for CTL-induced killing, may have a critical balance of these two properties.
authors.affiliation: Julia McFarlane Diabetes Research Centre, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada;
authors.forename: Jinguo
authors.initials: J
authors.lastname: Wang
authors.affiliation: Julia McFarlane Diabetes Research Centre, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada;
authors.forename: Roopa Hebbandi
authors.initials: RH
authors.lastname: Nanjundappa
authors.affiliation: Julia McFarlane Diabetes Research Centre, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada;
authors.forename: Afshin
authors.initials: A
authors.lastname: Shameli
authors.affiliation: Julia McFarlane Diabetes Research Centre, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada;
authors.forename: Xavier
authors.initials: X
authors.lastname: Clemente-Casares
authors.affiliation: Julia McFarlane Diabetes Research Centre, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada;
authors.forename: Jun
authors.initials: J
authors.lastname: Yamanouchi
authors.affiliation: Alberta Diabetes Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada; Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada; Division of Dermatology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada;
authors.forename: John F
authors.initials: JF
authors.lastname: Elliott
authors.affiliation: Department of Immunology, Monash University, Alfred Hospital Medical Research and Education Precinct, Melbourne, Victoria 3004, Australia; and.
authors.forename: Robyn
authors.initials: R
authors.lastname: Slattery
authors.affiliation: Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Serra
authors.affiliation: Julia McFarlane Diabetes Research Centre, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada; Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona 08036, Spain psantama@ucalgary.ca.
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D017209:Apoptosis / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009336:Necrosis
chemical_list: D001324:Autoantigens; D015395:Histocompatibility Antigens Class I; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse