Act1, a negative regulator in CD40- and BAFF-mediated B cell survival

Immunity. 2004 Oct;21(4):575-87. doi: 10.1016/j.immuni.2004.09.001.

Abstract

TNF receptor (TNFR) superfamily members, CD40, and BAFFR play critical roles in B cell survival and differentiation. Genetic deficiency in a novel adaptor molecule, Act1, for CD40 and BAFF results in a dramatic increase in peripheral B cells, which culminates in lymphadenopathy and splenomegaly, hypergammaglobulinemia, and autoantibodies. While the B cell-specific Act1 knockout mice displayed a similar phenotype with less severity, the pathology of the Act1-deficient mice was mostly blocked in CD40-Act1 and BAFF-Act1 double knockout mice. CD40- and BAFF-mediated survival is significantly increased in Act1-deficent B cells, with stronger IkappaB phosphorylation, processing of NF-kappaB2 (p100/p52), and activation of JNK, ERK, and p38 pathways, indicating that Act1 negatively regulates CD40- and BAFF-mediated signaling events. These findings demonstrate that Act1 plays an important role in the homeostasis of B cells by attenuating CD40 and BAFFR signaling.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autoantibodies / blood
  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Blotting, Southern
  • Blotting, Western
  • CD40 Antigens / immunology*
  • CD40 Antigens / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism*
  • Cell Survival / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Hypergammaglobulinemia / etiology
  • I-kappa B Proteins / immunology
  • I-kappa B Proteins / metabolism
  • Immunohistochemistry
  • Immunoprecipitation
  • JNK Mitogen-Activated Protein Kinases / immunology
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lymphoid Tissue / cytology
  • Lymphoid Tissue / immunology
  • Lymphoid Tissue / pathology
  • MAP Kinase Kinase 4
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase Kinases / immunology
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction / immunology
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / immunology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Autoantibodies
  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • CD40 Antigens
  • Carrier Proteins
  • I-kappa B Proteins
  • Membrane Proteins
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor
  • TNFRSF13C protein, human
  • TNFSF13B protein, human
  • Tnfsf13b protein, mouse
  • Tumor Necrosis Factor-alpha
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases