Context-specific BAFF-R signaling by the NF-κB and PI3K pathways.
BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff(-/-) animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner.
Program on Inflammatory Diseases, Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Julia
J
Jellusova
Ana V
AV
Miletic
Matthew H
MH
Cato
Wai-Wai
WW
Lin
Yinling
Y
Hu
Gail A
GA
Bishop
Mark J
MJ
Shlomchik
Robert C
RC
Rickert
D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology*; D053265:B-Cell Activation Factor Receptor / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D004789:Enzyme Activation; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000235:genetics; D038041:Lymphopoiesis / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000276:immunology; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000276:immunology
D018941:Antigens, CD19; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D052003:NF-kappa B p52 Subunit; D048008:TNF Receptor-Associated Factor 3; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse