Crystal structure of extracellular human BAFF, a TNF family member that stimulates B lymphocytes

Karpusas, Michael; Cachero, Teresa G.; Qian, Fang; Boriack-Sjodin, Ann; Mullen, Colleen; Strauch, Kathy; Hsu, Yen-Ming; Kalled, Susan L.

doi:10.1006/jmbi.2001.5296

Cited by 126 publications

(84 citation statements)

References 47 publications

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“…Recombinant human BAFF was produced as described (39). BAFF and recombinant human IL-4 (R&D Systems) were used at optimal concentrations of 50 and 5 ng/ml, respectively.…”

Section: Cytokines and Additional Culture Reagentsmentioning

confidence: 99%

Innate Immunity and Human B Cell Clonal Expansion: Effects on the Recirculating B2 Subpopulation

Mongini

Inman

Han

et al. 2005

The Journal of Immunology

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Foci of autoantigen-specific B lymphocytes in nonlymphoid tissues have been associated with development of autoimmune disease. To better understand the genesis of such ectopic lymphoid tissue, this study investigated whether several B cell-tropic innate immune system molecules, known to be elevated in response to inflammatory stimuli, can cooperate in fostering the T cell-independent clonal expansion of mature human B2 cells under conditions of limiting BCR engagement. Notable synergy was observed between BCR coligation with the C3dg-binding CD21/CD19 costimulatory complex, B cell-activating factor belonging to the TNF family (BAFF), and IL-4 in generating B cell progeny with sustained CD86 and DR expression. The synergy was observed over a wide range of BCR:ligand affinities and involved: 1) cooperative effects at promoting early cell cycle progression and viability; 2) BCR:CD21 coligation-promoted increases in BAFF receptors that were highly regulated by IL-4; 3) reciprocal effects of IL-4 and BAFF at dampening daughter cell apoptosis typical of stimulation by BCR:CD21 and either cytokine alone; and 4) BAFF-sustained expression of antiapoptotic Mcl-1 within replicating lymphoblasts. The results suggest that significant clonal proliferation of recirculating B2 cells occurs upon limited binding to C3dg-coated Ag in an inflammatory in vivo milieu containing both BAFF and IL-4. When rare autoantigen-presenting B cells undergo such expansions, both B cell and T cell autoimmunity may be promoted.

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“…Recombinant human BAFF was produced as described (39). BAFF and recombinant human IL-4 (R&D Systems) were used at optimal concentrations of 50 and 5 ng/ml, respectively.…”

Section: Cytokines and Additional Culture Reagentsmentioning

confidence: 99%

Innate Immunity and Human B Cell Clonal Expansion: Effects on the Recirculating B2 Subpopulation

Mongini

Inman

Han

et al. 2005

The Journal of Immunology

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“…Like most members of the TNF family, the extracellular domain of TALL-1 can be cleaved to form a soluble cytokine (2). Crystal structure studies suggest that soluble TALL-1 (sTALL-1) 3 contains an unique "flap" region that is important for its virus-like assembly, receptor binding, and biological activities (7)(8)(9).…”

Section: Tnfr-associatedmentioning

confidence: 99%

TNFR-Associated Factor-3 Is Associated With BAFF-R and Negatively Regulates BAFF-R-Mediated NF-κB Activation and IL-10 Production

Shu

2002

The Journal of Immunology

136

126

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TALL-1 is a member of the TNF family that is critically involved in B cell survival, maturation, and progression of lupus-like autoimmune diseases. TALL-1 has three receptors, including BCMA, TACI, and BAFF-R, which are mostly expressed by B lymphocytes. Gene knockout studies have indicated that BAFF-R is the major stimulatory receptor for TALL-1 signaling and is required for normal B cell development. The intracellular signaling mechanisms of BAFF-R are not known. In this report, we attempted to identify BAFF-R-associated downstream proteins by yeast two-hybrid screening. This effort identified TNFR-associated factor (TRAF)3 as a protein specifically interacting with BAFF-R in yeast two-hybrid assays. Coimmunoprecipitation experiments indicated that BAFF-R interacts with TRAF3 in B lymphoma cells and this interaction is stimulated by TALL-1 treatment. Domain mapping experiments indicated that both a 6-aa membrane proximal region and the C-terminal 35 aa of BAFF-R are required for its interaction with TRAF3. Moreover, overexpression of TRAF3 inhibits BAFF-R-mediated NF-κB activation and IL-10 production. Taken together, our findings suggest that TRAF3 is a negative regulator of BAFF-R-mediated NF-κB activation and IL-10 production.

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“…[7][8][9] Members of the TNF family usually assemble as trimers, 10 but soluble BAFF was crystallized both as a trimer and as a virus-like structure resulting from the ordered assembly of 20 trimers through an unusually long loop of BAFF between ␤-sheets D and E (DE loop). 11,12 Although the physiologic relevance of BAFF 60-mer has not been studied, recent work showed that BAFF 60-mer was also produced by cells expressing BAFF endogenously and that the 60-mer was moderately more potent than the 3-mer at costimulating BCR-induced thymidine uptake in primary B cells. 13 APRIL, a close homolog of BAFF, can also costimulate B cells but requires oligomerization to do so.…”

Section: Introductionmentioning

confidence: 99%

TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts

Bossen

Cachero

Tardivel

et al. 2008

Blood

257

270

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The cytokine BAFF binds to the receptors TACI, BCMA, and BAFF-R on B cells, whereas APRIL binds to TACI and BCMA only. The signaling properties of soluble trimeric BAFF (BAFF 3-mer) were compared with those of higher-order BAFF oligomers. All forms of BAFF bound BAFF-R and TACI, and elicited BAFF-R-dependent signals in primary B cells. In contrast, signaling through TACI in mature B cells or plasmablasts was only achieved by higher-order BAFF and APRIL oligomers, all of which were also po-tent activators of a multimerization-dependent reporter signaling pathway. These results indicate that, although BAFF-R and TACI can provide B cells with similar signals, only BAFF-R, but not TACI, can respond to soluble BAFF 3-mer, which is the main form of BAFF found in circulation. BAFF 60-mer, an efficient TACI agonist, was also detected in plasma of BAFF transgenic and nontransgenic mice and was more than 100-fold more active than BAFF 3-mer for the activation of multimerization-dependent signals. TACI supported survival of activated B cells and plasmablasts in vitro, providing a rational basis to explain the immunoglobulin deficiency reported in TACI-deficient persons

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Crystal structure of extracellular human BAFF, a TNF family member that stimulates B lymphocytes

Cited by 126 publications

References 47 publications

Innate Immunity and Human B Cell Clonal Expansion: Effects on the Recirculating B2 Subpopulation

Innate Immunity and Human B Cell Clonal Expansion: Effects on the Recirculating B2 Subpopulation

TNFR-Associated Factor-3 Is Associated With BAFF-R and Negatively Regulates BAFF-R-Mediated NF-κB Activation and IL-10 Production

TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts

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