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

Abstract

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

The Design and Characterization of Receptor-selective APRIL Variants

“…Regeneration of the anti-FLAG antibody surface was carried out with a 10-min injection at 30 l/min of a mixture of one-third volume of TBS, pH 11. Generation of Jurkat-BCMA:Fas and TACI:Fas Reporter Cells and Killing Assay-Jurkat-BCMA:Fas-2309 cl13 reporter cells were generated as described (28). TACI:Fas Jurkat cell reporter cell lines were generated essentially as described previously for EDAR:Fas cells (29).…”

“…6) yet stimulated small amounts of IgA. This might be due to the survival of a small population of preexisting IgA-producing cells (28), perhaps long lived plasma cells shown to depend on BCMA (4). On the other hand, the TACI-selective variants produced higher IgA levels than R206E, despite their lower affinity for BCMA.…”

“…R206E Shows Specificity for BCMA, whereas D132F and D132Y Show Selectivity toward TACI-In order to study receptor selectivity of APRIL variants in a standardized cell-based assay, BCMA:Fas-and TACI:Fas-expressing Jurkat cells were used as a reporter system (28). In this assay, binding of APRIL to chimeric receptors triggers the proapoptotic Fas signaling pathway, leading to cell death.…”

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

“…APRIL promotes B cell and plasma cell activation and survival and plays important roles in immunoglobulin class switching and antigen presentation (9)(10)(11). BLyS promotes B cell survival and maturation (12)(13)(14)(15).…”

BAFF/BLyS inhibitors: A new prospect for treatment of systemic lupus erythematosus

“…On the other hand, loss of TACI in mice leads to defective B cell responses to T-independent antigens (21,22). Proliferative signals through TACI do not occur efficiently in response to BAFF 3-mers (the most prevalent form of BAFF in the circulation), but do to BAFF 60-mers and membrane-bound BAFF (23).…”