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- Title
Receptor-specific regulation of B-cell susceptibility to Fas-mediated apoptosis and a novel Fas apoptosis inhibitory molecule.
- Authors
Rothstein, Thomas L.; Xuemei Zhong; Schram, Brian R.; Negm, Robert S.; Donohoe, Terrence J.; Cabral, Deborah S.; Foote, Linda C.; Schneider, Thomas J.
- Abstract
The susceptibility of primary B cells to Fas (APO-1, CD95)-mediated apoptosis is modulated by signals derived from additional surface receptors: CD40 engagement produces upregulation on Fas expression and marked sensitivity of Fas-induced cell death, whereas antigen receptor engagement, or interleukin-4 receptor (IL-4R) engagement, inhibits Fas killing and thereby produces Fas resistance, even in otherwise susceptible, CD40-stimulated targets. Surface immunoglobulin (sIg) and IL-4R utilize distinct signaling pathways to produce Fas resistance that rely on protein Kinase C and signal transducer and activator of transcription 6, respectively. sIg signaling for inducible Fas resistance requires nuclear factor-κB and depends on new macromolecular synthesis. Proximate mediators for Fas resistance include the known anti-apoptotic gene products BcL-xL and FLIP (but not Btk), and a novel anti-apoptotic gene that encodes Fas apoptosis inhibitory molecule (FAIM). FAIM was identified by differential display and was cloned as two alternatively spliced forms: FAIM-S is broadly expressed, whereas faim-L expression is tissue specific, faim is highly evolutionarily conserved, suggesting an important function throughout phylogeny. Inducible resistance to Fas-mediated apoptosis is speculated to protect antigen-specific B cells during potentially dangerous interactions with FasL-bearing T cells; the elevated sIg-signaling threshold for inducible Fas resistance in autoreactive, tolerant B cells would insure against autoimmunity. However, aberrant acquisition of Fas resistance may allow autoreactive B cells to escape Fas deletion and malignant lymphocytes to thwart antitumor immunity.
- Subjects
B cells; APOPTOSIS; ANTIGENS; CELL receptors
- Publication
Immunological Reviews, 2000, Vol 176, Issue 1, p116
- ISSN
0105-2896
- Publication type
Article
- DOI
10.1034/j.1600-065X.2000.00616.x