We sought to define the consequence of the C76R mutation on TACI function in mice that express both wild-type TACI and the murine C76R mutant.
Transgenic mice that express murine TACI C76R, the counterpart of human TACI C104R, on the TACI+/− B6/129 background (C76R/TACI+/− mice) were constructed. Serum immunoglobulins and antibody responses to the type II T-independent antigen trinitrophenylated (TNP)-Ficoll were determined by means of ELISA. B-cell proliferation in response to a proliferation-inducing ligand was determined based on tritiated thymidine incorporation into DNA. IgG1 secretion by B cells in response to a proliferation-inducing ligand plus IL-4 was determined by means of ELISA.
C76R/TACI+/− mice had significantly impaired antibody responses to the type II T-independent antigen TNP-Ficoll compared with TACI+/+ B6/129 control animals, and their B cells were impaired in their capacity to proliferate and secrete IgG1 in response to TACI ligation. Unexpectedly, TACI+/− mice had similarly impaired B-cell function as C76R/TACI+/− littermates. Impaired TACI function caused by haploinsufficiency was confirmed in TACI+/− mice on the C57BL/6 background.
These results suggest that the human TACI mutant C104R might impair TACI function in heterozygotes through haploinsufficiency.