title: The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity.
abstract: Dendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (Tnfaip3) determines the activation threshold of DCs, via control of canonical NF-κB activation. Tnfaip3(fl/fl)Cd11c-cre(+) mice lacking A20 in DCs demonstrated spontaneous proliferation of conventional and double-negative T cells, their conversion to interferon-γ (IFN-γ)-producing effector cells, and expansion of plasma cells. They developed ds-DNA antibodies, nephritis, the antiphospholipid syndrome, and lymphosplenomegaly-features of systemic lupus erythematosus-and extramedullary hematopoiesis. A20-deficient DCs were resistant to apoptosis, caused by increased sensitivity to CD40L and RANKL prosurvival signals and upregulation of antiapoptotic proteins Bcl-2 and Bcl-x. They captured injected apoptotic cells more efficiently, resisted the inhibitory effects of apoptotic cells, and induced self-reactive effector lymphocytes. Because genetic polymorphisms in TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity.
authors: Laboratory of Immunoregulation, Department of Pulmonary Medicine, University Hospital Gent, 9000 Gent, Belgium.
authors: Mirjam
authors: M
authors: Kool
authors: Geert
authors: G
authors: van Loo
authors: Wim
authors: W
authors: Waelput
authors: Sofie
authors: S
authors: De Prijck
authors: Femke
authors: F
authors: Muskens
authors: Mozes
authors: M
authors: Sze
authors: Jens
authors: J
authors: van Praet
authors: Filipe
authors: F
authors: Branco-Madeira
authors: Sophie
authors: S
authors: Janssens
authors: Boris
authors: B
authors: Reizis
authors: Dirk
authors: D
authors: Elewaut
authors: Rudi
authors: R
authors: Beyaert
authors: Hamida
authors: H
authors: Hammad
authors: Bart N
authors: BN
authors: Lambrecht
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D017209:Apoptosis / Q000235:genetics; D015551:Autoimmunity / Q000235:genetics; D023201:CD40 Ligand / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D000974:Antibodies, Antinuclear; D047908:Intracellular Signaling Peptides and Proteins; D053245:RANK Ligand; D023201:CD40 Ligand; D007371:Interferon-gamma; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse