The Ubiquitin Modifying Enzyme A20 Restricts B Cell Survival and Prevents Autoimmunity

A20 is a ubiquitin modifying enzyme that restricts NF-κB signals and protects cells against tumor necrosis factor (TNF)-induced programmed cell death. Given recent data linking A20 ( TNFAIP3) with human B cell lymphomas and systemic lupus erythematosus (SLE), we have generated mice bearing a floxed allele of Tnfaip3 to interrogate A20's roles in regulating B cell functions. A20-deficient B cells are hyperresponsive to multiple stimuli and display exaggerated NF-κB responses to CD40-induced signals. Mice expressing absent or hypomorphic amounts of A20 in B cells possess elevated numbers of germinal center B cells, autoantibodies, and glomerular immunoglobulin deposits. A20-deficient B cells are resistant to Fas-mediated cell death, probably due to increased expression of NF-κB-dependent antiapoptotic proteins such as Bcl-x. These findings show that A20 can restrict B cell survival, whereas A20 protects other cells from TNF-induced cell death. Our studies demonstrate how reduced A20 expression predisposes to autoimmunity. ► A20 expression in B cells prevents autoimmunity ► A20 restricts CD40-triggered NF-κB signals ► Hypomorphic A20 expression in B cells leads to elevated germinal center B cells ► A20-deficient B cells express more Bcl-x and resist Fas mediated cell death