The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity

Mirjam Kool; Geert van Loo; Wim Waelput; Sofie De Prijck; Femke Muskens; Mozes Sze; Jens van Praet; Filipe Branco-Madeira; Sophie Janssens; Boris Reizis; Dirk Elewaut; Rudi Beyaert; Hamida Hammad; Bart N Lambrecht

doi:10.1016/j.immuni.2011.05.013

The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity

Immunity. 2011 Jul 22;35(1):82-96. doi: 10.1016/j.immuni.2011.05.013. Epub 2011 Jun 30.

Authors

Mirjam Kool¹, Geert van Loo, Wim Waelput, Sofie De Prijck, Femke Muskens, Mozes Sze, Jens van Praet, Filipe Branco-Madeira, Sophie Janssens, Boris Reizis, Dirk Elewaut, Rudi Beyaert, Hamida Hammad, Bart N Lambrecht

Affiliation

¹ Laboratory of Immunoregulation, Department of Pulmonary Medicine, University Hospital Gent, 9000 Gent, Belgium.

PMID: 21723156
DOI: 10.1016/j.immuni.2011.05.013

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Antinuclear / blood
Apoptosis / genetics
Autoimmunity / genetics
CD40 Ligand / metabolism
Cell Proliferation
Cells, Cultured
Cysteine Endopeptidases / genetics
Cysteine Endopeptidases / immunology
Cysteine Endopeptidases / metabolism*
Dendritic Cells / immunology
Dendritic Cells / metabolism*
Dendritic Cells / pathology
Humans
Interferon-gamma / metabolism
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / immunology
Intracellular Signaling Peptides and Proteins / metabolism*
Lupus Erythematosus, Systemic / blood
Lupus Erythematosus, Systemic / immunology*
Mice
Mice, Mutant Strains
Mutation / genetics
Plasma Cells / immunology
Plasma Cells / metabolism*
Plasma Cells / pathology
RANK Ligand / metabolism
T-Lymphocytes / immunology
T-Lymphocytes / metabolism*
T-Lymphocytes / pathology
Tumor Necrosis Factor alpha-Induced Protein 3

Substances

Antibodies, Antinuclear
Intracellular Signaling Peptides and Proteins
RANK Ligand
CD40 Ligand
Interferon-gamma
Tumor Necrosis Factor alpha-Induced Protein 3
Cysteine Endopeptidases
Tnfaip3 protein, mouse