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. Tnfaip3fl/flCd11c-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.

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Persistent URL dx.doi.org/10.1016/j.immuni.2011.05.013, hdl.handle.net/1765/31464
Citation
Kool, M, van Loo, G, Waelput, W, de Prijck, S, Muskens, F, Sze, M, … Lambrecht, B.N.M. (2011). The ubiquitin-editing protein a20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity, 35(1), 82–96. doi:10.1016/j.immuni.2011.05.013