Context-specific BAFF-R Signaling by the NF-κB and PI3K Pathways

Cell Rep. 2013 Nov 27;5(4):1022-35. doi: 10.1016/j.celrep.2013.10.022. Epub 2013 Nov 14.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / immunology
  • B-Cell Activating Factor / genetics
  • B-Cell Activating Factor / immunology*
  • B-Cell Activation Factor Receptor / immunology
  • B-Lymphocytes / immunology
  • Cell Proliferation
  • Cell Survival / immunology
  • Cells, Cultured
  • Enzyme Activation
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / immunology*
  • Lymphocyte Activation / immunology
  • Lymphoma, B-Cell / genetics
  • Lymphopoiesis / immunology*
  • Mice
  • Mice, Knockout
  • NF-kappa B p52 Subunit / immunology
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / immunology
  • Phosphatidylinositol 3-Kinases / immunology*
  • Signal Transduction / immunology
  • TNF Receptor-Associated Factor 3 / genetics
  • TNF Receptor-Associated Factor 3 / immunology

Substances

  • Antigens, CD19
  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • NF-kappa B p52 Subunit
  • TNF Receptor-Associated Factor 3
  • Tnfrsf13c protein, mouse
  • Tnfsf13b protein, mouse
  • Phosphatidylinositol 3-Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • PTEN Phosphohydrolase
  • Pten protein, mouse