Ligand-independent oligomerization of TACI is controlled by the transmembrane domain and regulates proliferation of activated B cells

In mature B cells, TACI controls class-switch recombination and differentiation into plasma cells during T cell-independent antibody responses. TACI binds the ligands BAFF and APRIL. Approximately 10% of patients with common variable immunodeficiency (CVID) carry TACI mutations, of which A181E and C172Y are in the transmembrane domain. Residues A181 and C172 are located on distinct sides of the transmembrane helix, which is predicted by molecular modeling to spontaneously assemble into trimers and dimers. In human B cells, these mutations impair ligand-dependent (C172Y) and -independent (A181E) TACI multimerization and signaling, as well as TACI-enhanced proliferation and/or IgA production. Genetic inactivation of TACI in primary human B cells impaired survival of CpG-activated cells in the absence of ligand. These results identify the transmembrane region of TACI as an active interface for TACI multimerization in signal transduction, in particular for ligand-independent signals. These functions are perturbed by CVID-associated mutations. [Display omitted] •TACI transmembrane domain associates via distinct trimeric and dimeric interfaces•CVID-associated mutation A181E and C172Y affect the trimeric and dimeric interfaces•TACI transmembrane domain regulates ligand-dependent and -independent signaling•Spontaneous TACI signals help proliferation and IgA production of activated B cells Smulski et al. characterize immunodeficiency-associated mutations in the transmembrane domain of TACI that perturb the complex self-assembly of this receptor, impinging on auto- or ligand-induced signaling. Oligomerization of the transmembrane domain of TACI plays an active role in the proliferation of activated B cells and in antibody production.