Critical role of B cell lymphoma 10 in BAFF-regulated NF-κB activation and survival of anergic B cells.

Anergy is a key physiological mechanism for restraining self-reactive B cells. A marked portion of peripheral B cells are anergic B cells that largely depend on BAFF for survival. BAFF activates the canonical and noncanonical NF-kappa B pathways, both of which are required for B cell survival. In this study we report that deficiency of the adaptor protein B cell lymphoma 10 (Bcl10) impaired the ability of BAFF to support B cell survival in vitro, and it specifically increased apoptosis in anergic B cells in vivo, dramatically reducing anergic B cells in mice. Bcl10-dependent survival of self-reactive anergic B cells was confirmed in the Ig hen egg lysozyme/soluble hen egg lysozyme double-transgenic mouse model of B cell anergy. Furthermore, we found that BAFF stimulation induced Bcl10 association with I kappa B kinase beta, a key component of the canonical NF-kappa B pathway. Consistently, Bcl10-deficient B cells were impaired in BAFF-induced I kappa B alpha phosphorylation and formation of nuclear p50/c-Rel complexes. Bcl10-deficient B cells also displayed reduced expression of NF-kappa B2/p100, severely reducing BAFF-induced nuclear accumulation of noncanonical p52/RelB complexes. Consequently, Bcl10-deficient B cells failed to express Bcl-x(L), a BAFF-induced NF-kappa B target gene. Taken together, these data demonstrate that Bcl10 controls BAFF-induced canonical NF-kappa B activation directly and noncanonical NF-kappa B activation indirectly. The BAFF-R/Bcl10/NF-kappa B signaling axis plays a critical role in peripheral B cell tolerance by regulating the survival of self-reactive anergic B cells. The Journal of Immunology, 2012, 189: 5185-5193.