Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor.
BLys , a key cytokine that sustains B cell maturation and tolerance, binds three receptors: BR3, BCMA, and TACI. Results from knockout mice implicate a major functional role for BR3 and a redundant one for BCMA in B cell function. TACI's role is controversial based on defects in TI antibody responses accompanied by B cell hyperplasia in knockout mice. We have presently characterized a precise role for TACI in vivo. TACI(-/-) mice develop fatal autoimmune glomerulonephritis, proteinurea, and elevated levels of circulating autoantibodies. Treatment of B cells with TACI agonistic antibodies inhibits proliferation in vitro and activation of a chimeric receptor containing the TACI intracellular domain induces apoptosis. These results demonstrate the critical requirement for TACI in regulating B cell homeostasis.
Seshasayee
Dhaya
D
Department of Immunology, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
Valdez
Patricia
P
Yan
Minhong
M
Dixit
Vishva M
VM
Tumas
Daniel
D
Grewal
Iqbal S
IS
D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053265:B-Cell Activation Factor Receptor; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D053303:Transmembrane Activator and CAML Interactor Protein
D053265:B-Cell Activation Factor Receptor; C120197:BLyS receptor; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C108467:TNFRSF13B protein, human; C435926:TNFRSF13C protein, human; C486361:Tnfrsf13b protein, mouse; C486662:Tnfrsf13c protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein