Identification of a novel receptor for B lymphocyte stimulator that is mutated in a mouse strain with severe B cell deficiency.
BLyS (also called BAFF, TALL-1, THANK, and zTNF4), a TNF superfamily member, binds two receptors, TACI and BCMA, and regulates humoral immune responses [1-7]. These two receptors also bind APRIL [7-10], another TNF superfamily member. The results from TACI(-/-) and BCMA(-/-) mice suggest the existence of additional receptor(s) for BLyS. The TACI knockout gives the paradoxical result of B cells being hyperresponsive, suggesting an inhibitory role for this receptor [11, 12], while BCMA null mice have no discernable phenotype [13]. Here we report the identification of a third BLyS receptor (BR3; BLyS receptor 3). This receptor is unique in that, in contrast to TACI and BCMA, BR3 only binds BLyS. Treatment of antigen-challenged mice with BR3-Fc inhibited antibody production, indicating an essential role for BLyS, but not APRIL, in this response. A critical role for BR3 in B cell ontogeny is underscored by our data showing that the BR3 gene had been inactivated by a discrete, approximately 4.7 kb gene insertion event that disrupted the 3' end of the BR3 gene in A/WySnJ mice, which lack peripheral B cells.
Yan
M
M
Department of Molecular Oncology, Genentech, South San Francisco, CA 94080, USA.
Brady
J R
JR
Chan
B
B
Lee
W P
WP
Hsu
B
B
Harless
S
S
Cancro
M
M
Grewal
I S
IS
Dixit
V M
VM
D000595:Amino Acid Sequence; D000818:Animals; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D001402:B-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D001483:Base Sequence; D019556:COS Cells; D002522:Chlorocebus aethiops; D018076:DNA, Complementary; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D018124:Receptors, Tumor Necrosis Factor / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D053303:Transmembrane Activator and CAML Interactor Protein; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; C120197:BLyS receptor; D018076:DNA, Complementary; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C108467:TNFRSF13B protein, human; C435926:TNFRSF13C protein, human; C086966:TNFRSF17 protein, human; C505719:TNFSF13B protein, human; C486361:Tnfrsf13b protein, mouse; C486662:Tnfrsf13c protein, mouse; C490176:Tnfrsf17 protein, mouse; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein; D014409:Tumor Necrosis Factor-alpha