Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID)

B cells from patients with common variable immunodeficiency (CVID) who are heterozygous for transmembrane activator and CAML interactor (TACT) mutation C104R, which abolishes ligand binding, fail to produce Igs in response to TACT ligand. It is not known whether this is due to haploinsufficiency or dominant interference. Using in vitro transfection assays, here we demonstrate that C104R and the corresponding murine TACT mutant, C76R, which also does not bind ligand, dominantly interfere with TACT signaling. This effect was dependent on preassociation of the mutants with WT TACT in the absence of ligand. The mutants did not interfere with ligand binding by WT TACT, suggesting that they may act by disrupting ligand-induced receptor rearrangement and signaling. This work demonstrates that TACT preassembles as an oligomeric complex prior to ligand binding and provides a mechanistic insight into how the heterozygous C104R TACT mutation can potentially lead to CVID.