title: Proteasome immunosubunits protect against the development of CD8 T cell-mediated autoimmune diseases.
abstract: Exposure of cells to inflammatory cytokines induces the expression of three proteasome immunosubunits, two of which are encoded in the MHC class II region. The induced subunits replace their constitutive homologs in newly formed "so-called" immunoproteasomes. Immunosubunit incorporation enhances the proteasome's proteolytic activity and modifies the proteasome's cleavage-site preferences, which improves the generation of many MHC class I-presented peptides and shapes the fine specificity of pathogen-specific CD8 T cell responses. In this article, we report on a second effect of immunoproteasome formation on CD8 T cell responses. We show that mice deficient for the immunosubunits β5i/low molecular mass polypeptide (LMP7) and β2i/multicatalytic endopeptidase complex-like-1 develop early-stage multiorgan autoimmunity following irradiation and bone marrow transplantation. Disease symptoms are caused by CD8 T cells and are transferable into immunosubunit-deficient, RAG1-deficient mice. Moreover, using the human Type 1 Diabetes Genetics Consortium MHC dataset, we identified two single nucleotide polymorphisms within the β5i/LMP7-encoding gene sequences, which were in strong linkage disequilibrium, as independent genetic risk factors for type 1 diabetes development in humans. Strikingly, these single nucleotide polymorphisms significantly enhanced the risk conferred by HLA haplotypes that were previously shown to predispose for type 1 diabetes. These data suggested that inflammation-induced immunosubunit expression in peripheral tissues constitutes a mechanism that prevents the development of CD8 T cell-mediated autoimmune diseases.
authors.affiliation: Division of Immunology, Faculty of Veterinary Medicine, University of Utrecht, 3584CL Utrecht, The Netherlands.
authors.forename: Dietmar M W
authors.initials: DM
authors.lastname: Zaiss
authors.forename: Cornelis P J
authors.initials: CP
authors.lastname: Bekker
authors.forename: Andrea
authors.initials: A
authors.lastname: Gröne
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
authors.forename: Alice J A M
authors.initials: AJ
authors.lastname: Sijts
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000276:immunology*; D012307:Risk Factors
chemical_list: C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex