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¹ Department of Microbiology, University of Washington, Seattle, WA 98195
² Department of Immunology, University of Washington, Seattle, WA 98195

CORRESPONDENCE Andrew Craxton: andyuk{at}u.washington.edu

The B cell activating factor belonging to the tumor necrosis factor family (BAFF) is required for B cell survival and maturation. The mechanisms by which BAFF mediates B cell survival are less understood. We found that BAFF and a proliferation-inducing ligand (APRIL), which are related, block B cell antigen receptor (BCR)–induced apoptosis upstream of mitochondrial damage, which is consistent with a role for Bcl-2 family proteins. BCR ligation strongly increased expression of the proapoptotic Bcl-2 homology 3–only Bcl-2 protein Bim in both WEHI-231 and splenic B cells, and increases in Bim were reversed by BAFF or APRIL. Small interfering RNA vector–mediated suppression of Bim blocked BCR-induced apoptosis. BAFF also induced Bim phosphorylation and inhibited BCR-induced association of Bim with Bcl-2. BAFF induced delayed but sustained stimulation of extracellular signal–regulated kinase (ERK) and its activators, mitogen-activated protein kinase/ERK activating kinase (MEK) and c-Raf, and MEK inhibitors promoted accumulation and dephosphorylation of Bim. These results suggest that BAFF inhibits BCR-induced death by down-regulating Bim via sustained ERK activation, demonstrating that BAFF directly regulates Bim function. Although transitional immature type 1 (T1) B cell numbers are normal in Bim^–/– mice, T2 and follicular mature B cells are elevated and marginal zone B cells are reduced. Our results suggest that mature B cell homeostasis is maintained by BAFF-mediated regulation of Bim.

Abbreviations used: APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor belonging to the TNF family; BCMA, B cell maturation antigen; BCR, B cell antigen receptor; BH3, Bcl-2 homology 3; m, mitochondrial membrane potential; DUSP, dual-specificity phosphatase; ERK, extracellular signal–regulated kinase; FO, follicular; FOP, FO precursor; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK activating kinase; MKP, MAPK phosphatase; MZ, marginal zone; MZP, MZ precursor; PARP, poly(ADP- ribose)polymerase; siRNA, small interfering RNA; T1, transitional immature type 1; TACI, transmembrane activator and cyclophilin ligand interactor.

A. Gruppi's present address is Immunology, Dept. of Clinical Biochemistry, Faculty of Chemical Sciences, National University of Cordoba, Cordoba 5000, Argentina.

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