| First Author | Kool M | Year | 2011 |
| Journal | Immunity | Volume | 35 |
| Issue | 1 | Pages | 82-96 |
| PubMed ID | 21723156 | Mgi Jnum | J:174380 |
| Mgi Id | MGI:5085950 | Doi | 10.1016/j.immuni.2011.05.013 |
| Citation | Kool M, et al. (2011) The ubiquitin-editing protein a20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity 35(1):82-96 |
| abstractText | 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-kappaB 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. |
