BAFF-R, a Newly Identified TNF Receptor That Specifically Interacts with BAFF (original) (raw)
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The Journal of Immunology, 2004
The cytokine TNF family member B cell-activating factor (BAFF; also termed BLyS) is essential for B cell generation and maintenance. Three receptors have been identified that bind to BAFF: transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI); B cell maturation Ag (BCMA); and BAFF-R. Recently, it was shown that A/WySnJ mice, which contain a dramatically reduced peripheral B cell compartment due to decreased B cell life span, express a mutant BAFF-R. This finding, together with normal or enhanced B cell generation in mice deficient for BCMA or TACI, respectively, suggested that the interaction of BAFF with BAFF-R triggers signals essential for the generation and maintenance of mature B cells. However, B cells in mice deficient for BAFF differ phenotypically and functionally from A/WySnJ B cells. Residual signaling through the mutant BAFF-R could account for these differences. Alternatively, dominant-negative interference by the mutant receptor could lead to an overestimation of the importance of BAFF-R. To resolve this issue, we generated BAFF-R-null mice. Baff-r ؊/؊ mice display strongly reduced late transitional and follicular B cell numbers and are essentially devoid of marginal zone B cells. Overexpression of Bcl-2 rescues mature B cell development in Baff-r ؊/؊ mice, suggesting that BAFF-R mediates a survival signal. CD21 and CD23 surface expression are reduced on mature Baff-r ؊/؊ B cells, but not to the same extent as on mature B cells in BAFF-deficient mice. In addition, we found that Baff-r ؊/؊ mice mount significant, but reduced, Ag-specific Ab responses and are able to form spontaneous germinal centers in mesenteric lymph nodes. The reduction in Ab titers correlates with the reduced B cell numbers in the mutant mice.
BAFF, a Novel Ligand of the Tumor Necrosis Factor Family, Stimulates B Cell Growth
Journal of Experimental Medicine, 1999
Members of the tumor necrosis factor (TNF) family induce pleiotropic biological responses, including cell growth, differentiation, and even death. Here we describe a novel member of the TNF family, designated BAFF (for B cell activating factor belonging to the TNF family), which is expressed by T cells and dendritic cells. Human BAFF was mapped to chromosome 13q32-34. Membrane-bound BAFF was processed and secreted through the action of a protease whose specificity matches that of the furin family of proprotein convertases. The expression of BAFF receptor appeared to be restricted to B cells. Both membrane-bound and soluble BAFF induced proliferation of anti-immunoglobulin M-stimulated peripheral blood B lymphocytes. Moreover, increased amounts of immunoglobulins were found in supernatants of germinal center-like B cells costimulated with BAFF. These results suggest that BAFF plays an important role as costimulator of B cell proliferation and function.
Journal of Experimental Medicine, 2000
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.
BAFF Receptor Regulation of Peripheral B-Lymphocyte Survival and Development
BLyS Ligands and Receptors, 2009
B-lymphocyte homeostasis depends on exogenous signals for survival during development and in immune responses to invading pathogens. These signals are continually provided by either tonic or antigen-mediated BCR signals and other trophic factors. B-cell-activating factor (BAFF) has emerged as a key growth factor for B lymphocytes. Through its interaction with a TNF-R family member, BAFF-R or BR3, BAFF promotes survival of both immature and mature B cells. BAFF/BR3 interaction also facilitates BCR-induced B-cell proliferation. Thus, dysregulation of the signals emanating from these receptors leads to autoimmune disease, whereas interference with these signals leads to B-cell immunodeficiencies. Multiple signal transduction pathways, including those involving transcription factor NF-κB, appear to play critical roles in BAFF-mediated B-cell biological responses. Recent studies have revealed that BR3 and BCR are functionally linked and that Bruton's cytoplasmic tyrosine kinase (Btk)/NF-κB signaling plays an essential role in this process. Therefore, the primary objective of this article is to discuss BR3-signaling pathways, and the cooperation with BCR signals, that regulate B-cell survival during development and activation.
Cutting Edge: BAFF Regulates CD21/35 and CD23 Expression Independent of Its B Cell Survival Function
The Journal of Immunology, 2004
Herein we demonstrate that B cell-activating factor of the TNF family (BAFF), a B cell survival factor, also regulates CD21/35 and CD23 expression. BAFF blockade in wildtype mice down-modulates CD21/35 and CD23 on B cells while survival remains intact, and BAFF exposure causes elevated CD21/35 and CD23 expression. Similar downmodulation is observed in bcl-2-transgenic mice treated with a BAFF inhibitor. This is the first evidence that BAFF has a function independent of B cell survival. Reports using CD21/35 and CD23 expression to assess splenic B cell subsets in BAFF-null mice concluded a lack of B cells beyond the immature stage. Since CD21/35 and CD23 are inadequate for delineating B cell subpopulations in BAFF-null mice, we used expression of BAFF-R and several B cell markers to identify more mature splenic B cells in these mice. These data broaden our understanding of BAFF function and correct the view that BAFF-null mice lack mature B cells.
TNF cytokine family: More BAFFling complexities
Current Biology, 2001
Recent studies on BAFF, a member of the tumor necrosis factor family, and the discovery of a new BAFF receptor have revealed that this ligand–receptor pair is essential for B-cell survival and differentiation, holding promise for a better understanding and treatment of some autoimmune diseases and lymphomas.