Many members of the TNF family fulfill important roles related to the organization, function, and/or homeostasis of the immune system 1
. The recently identified TNF family member B cell activating factor (BAFF) (TNF and apoptosis ligand–related leukocyte-expressed ligand 1 [TALL-1]/TNF homologue that activates apoptosis, nuclear factor κB, and c-Jun NH2
-terminal kinase [THANK]/B lymphocyte stimulator [BlyS]; references 2345
) is expressed in monocytes, macrophages, and dendritic cells 235
and has been shown to bind to B cells and increase the proliferation of B cells in combination with an anti–B cell receptor antibody in vitro 25
. BAFF is a type II membrane protein and may act as either a membrane-bound or soluble form, the latter being generated by proteolytic cleavage at a furin consensus site 25
. Transgenic mice overexpressing BAFF have a greatly elevated number of mature B cells and an increased number of effector T cells in their spleen and mesenteric lymph nodes 6
. These mice display autoimmune-like manifestations including high levels of rheumatoid factors, circulating immune complexes, anti-DNA autoantibodies, and Ig deposition in the kidney 6
. However, splenic B cells from transgenic or control mice were found to proliferate at the same rate 6
, suggesting that BAFF, in addition to its ability to costimulate B cell proliferation in vitro, may have alternative functions.
B cell maturation antigen (BCMA) was first identified as part of a translocation event in a malignant T cell lymphoma patient 7
. Characterization of human BCMA identified it as a type I membrane protein primarily expressed in immune organs and mature B cell lines 78
. BCMA protein was localized to the Golgi apparatus in the U266 plasmacytoma cell line, which expresses high levels of BCMA 9
. Subsequent identification of the mouse BCMA gene and further motif analysis led to the prediction that BCMA is a member of the TNF receptor superfamily 10
Here, we show that BAFF is capable of interacting with the orphan TNF receptor, BCMA. We characterize the BAFF–BCMA interaction and show that injection of soluble BCMA-Ig fusion protein into mice leads to a dramatic reduction in the total number of B cells in the peripheral immune organs. This may be due to a B cell survival function of BAFF. Modulation of the peripheral B cell population using BCMA-Ig treatment may be efficacious in treating B cell–mediated disorders.