BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population

J S Thompson, P Schneider, S L Kalled, L Wang, E A Lefevre, T G Cachero, F MacKay, S A Bixler, M Zafari, Z Y Liu, S A Woodcock, F Qian, M Batten, C Madry, Y Richard, C D Benjamin, J L Browning, A Tsapis, J Tschopp, C Ambrose, J S Thompson, P Schneider, S L Kalled, L Wang, E A Lefevre, T G Cachero, F MacKay, S A Bixler, M Zafari, Z Y Liu, S A Woodcock, F Qian, M Batten, C Madry, Y Richard, C D Benjamin, J L Browning, A Tsapis, J Tschopp, C Ambrose

Abstract

The tumor necrosis factor (TNF) family member B cell activating factor (BAFF) binds B cells and enhances B cell receptor-triggered proliferation. We find that B cell maturation antigen (BCMA), a predicted member of the TNF receptor family expressed primarily in mature B cells, is a receptor for BAFF. Although BCMA was previously localized to the Golgi apparatus, BCMA was found to be expressed on the surface of transfected cells and tonsillar B cells. A soluble form of BCMA, which inhibited the binding of BAFF to a B cell line, induced a dramatic decrease in the number of peripheral B cells when administered in vivo. Moreover, culturing splenic cells in the presence of BAFF increased survival of a percentage of the B cells. These results are consistent with a role for BAFF in maintaining homeostasis of the B cell population.

Figures

Figure 1
Figure 1
The extracellular domain of BCMA interacts with BAFF. (A) Human BCMA-Ig and various control TNFR-Ig molecules were mixed with Flag-tagged TNF ligands, immunoprecipitated (IP) with protein A Sepharose, and analyzed by Western blot (WB). Receptor-Ig is revealed with anti–human IgG (top), and coimmunoprecipitating ligands are detected using anti-Flag M2 antibody (bottom). α, anti-. (B) Interaction of BAFF with BCMA assayed by surface plasmon resonance (BIAcore). (C) BCMA-Ig binds stable 293 cell line expressing surface full-length BAFF. The wild-type 293 cells or a stable cell line expressing BAFF (reference 2) were stained with media containing similar amounts of BCMA-Ig, TNFR2-Ig, TRAILR2-Ig, or control media using PE-conjugated anti-hIgG1 (left and middle). The presence of surface BAFF was detected using an anti-hBAFF rat mAb, 43.9 (reference 2; right). (D) BCMA-Ig blocks BAFF binding to Raji cells. Various concentrations of either BCMA-Ig or LTβR-Ig were preincubated with Flag-BAFF, then added to Raji cells. BAFF binding was detected with the anti-Flag M2 antibody and analyzed by flow cytometry.
Figure 2
Figure 2
Cell surface expression of BCMA in transfected and primary cells. (A) 293E cells were cotransfected with expression vectors for green fluorescent protein (GFP) and full-length human BCMA or a control plasmid. Surface expression of BCMA was detected with either an anti-BCMA antibody (top) or Flag-BAFF (bottom). (B) Human tonsillar B cells and the U266 plasmocytic cell line were stained with either anti-BCMA, control rabbit antibody, or Flag-BAFF, and were analyzed by flow cytometry.
Figure 3
Figure 3
Administration of BCMA-Ig reduces the peripheral B cell population. Adult Balb/c mice were treated with four intraperitoneal injections of BCMA-Ig or control Ig over a period of 11 d. At day 19, splenic B220+ B cells, CD4+ and CD8+ T cells, and Gr1+ and Mac-1+ populations were analyzed by flow cytometry. A representative mouse from each group is shown.
Figure 4
Figure 4
BAFF promotes the survival of splenocytes in vitro. (A) Forward (FSC) and side scatter (SSC) profiles of murine splenocytes in culture after 72 h in the presence or absence of BAFF. The R2 gate contains live cells (annexin V and propidium iodide negative). (B) Percentage of R2 cells surviving. BAFF concentration was 2 μg/ml, and fusion proteins were added at 10 μg/ml. This is a representative experiment of the assay done ∼10 times.

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