B-cell receptor and Fas-mediated signals for life and death

Immunol Rev. 2000 Aug;176:105-15. doi: 10.1034/j.1600-065x.2000.00502.x.


A series of B-cell lymphoma lines with an immature phenotype has been used as a model system to study molecular events associated with receptor ligation induced death. B-cell receptor (BCR) cross-linking with antibodies to membrane IgM (but not with anti IgD) induces c-Myc downregulation via nuclear factor kappaB inactivation and p27(Kip1) accumulation in these B lymphomas. Anti-mu-treated cells then undergo G1 arrest and die by apoptosis independent of Fas. Steroids and retinoids similarly downregulate c-Myc and induce apoptosis in these B cells and synergize with anti-mu. Rescue from apoptosis induced by anti-mu or steroids occurs with T-cell signals, like CD40L, or a broad-range caspase inhibitor, but only CD40L prevents the loss of c-Myc, p27 accumulation and growth arrest. Both IgM and IgD signaling lead to modulation of phosphatidylinositol 3-kinase (PI3K) signals, including the activation of p70(S6K), but this pathway recovers under anti-IgD treatment. Blockade of the PI3K pathway augments anti-mu-induced death and converts anti-delta to an apoptotic signal. Resistance to Fas-mediated death may be an important factor in B-cell transformation in vivo. Many of our panel of lymphomas are insensitive to Fas-mediated death signals, although all can form a death-inducing signaling complex (DISC). Additional studies suggest that some lymphomas can be blocked at the DISC complex by anti-apoptotic proteins, whereas others are inhibited downstream of caspase 8 activation. Anti-Ig treatment of a Fas-sensitive line, A20.2J, activated a number of genes whose products may block apoptosis proximally (like FLICE-inhibitory protein (FLIP1)) or at late points, such as bcl-2-family members. Our data suggest that B lymphomas develop multiple pathways of resistance to Fas-mediated signals during lymphomagenesis, in part via signaling through the BCR.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Cell Division
  • Humans
  • Immunoglobulin D / metabolism
  • Immunoglobulin M / metabolism
  • Lymphoma, B-Cell / immunology
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / pathology
  • Receptors, Antigen, B-Cell / metabolism*
  • Signal Transduction
  • Tumor Cells, Cultured
  • fas Receptor / metabolism*


  • Immunoglobulin D
  • Immunoglobulin M
  • Receptors, Antigen, B-Cell
  • fas Receptor