The Ubiquitin-Editing Protein A20 Prevents Dendritic Cell Activation, Recognition of Apoptotic Cells, and Systemic Autoimmunity

被引：209

作者：

Kool, Mirjam ^{[1
,2
,3
,4
]}

van Loo, Geert ^{[2
,3
]}

Waelput, Wim ^{[1
,5
]}

De Prijck, Sofie ^{[1
]}

Muskens, Femke ^{[4
]}

Sze, Mozes ^{[2
,3
]}

van Praet, Jens ^{[6
]}

Branco-Madeira, Filipe ^{[1
]}

Janssens, Sophie ^{[1
]}

Reizis, Boris ^{[7
]}

Elewaut, Dirk ^{[6
]}

Beyaert, Rudi ^{[2
,3
]}

Hammad, Hamida ^{[1
]}

Lambrecht, Bart N. ^{[1
,4
]}

机构：

[1] Ghent Univ Hosp, Immunoregulat Lab, Dept Pulm Med, B-9000 Ghent, Belgium

[2] VIB, Dept Mol Biomed Res, B-9052 Ghent, Belgium

[3] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium

[4] Erasmus Univ, Dept Pulm Med, Med Ctr, NL-3015 GE Rotterdam, Netherlands

[5] Univ Antwerp Hosp, Dept Pathol, B-2650 Edegem, Belgium

[6] Ghent Univ Hosp, Lab Mol Immunol, Dept Rheumatol, B-9000 Ghent, Belgium

[7] Columbia Univ, Dept Microbiol & Immunol, New York, NY 10032 USA

来源：

IMMUNITY | 2011年 / 35卷 / 01期

关键词：

NF-KAPPA-B; LUPUS-ERYTHEMATOSUS; MARGINAL ZONE; IN-VIVO; IMMUNE-RESPONSES; T-CELLS; DIFFERENTIATION; HOMEOSTASIS; TOLERANCE; ANTIGENS;

D O I：

10.1016/j.immuni.2011.05.013

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-kappa B 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-gamma (IFN-gamma)-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.

引用

页码：82 / 96

页数：15

共 44 条

[21] Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice [J].