Claudia Bossen1, Teresa G. Cachero2, Aubry Tardivel1, Karine Ingold1, Laure Willen1, Max Dobles2, Martin L. Scott2, Aris Maquelin1, Elodie Belnoue3, Claire-Anne Siegrist3, Stéphane Chevrier1, Hans Acha-Orbea1, Helen Leung4, Fabienne Mackay4, Jürg Tschopp1, Pascal Schneider1
1Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
2BiogenIdec, Cambridge, MA;
3Department of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland; and
4Garvan Institute of Medical Research, Darlinghurst, Australia
Tóm tắt
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.
