Receptor-specific regulation of B-cell susceptibility to Fas-mediated apoptosis and a novel Fas apoptosis inhibitory molecule

The susceptibility of primary B cells to Fas (APO-I, CD95)-mediated apoptos is is modulated by signals derived from additional surface receptors: CD40 engagement produces upregulation of Fas expression and marked sensitivity t o Fas-induced cell death, whereas antigen receptor engagement, or interleuk in-4 receptor (IL-4R) engagement, inhibits Fas killing and thereby produces Pas resistance, even in otherwise susceptible CD40-stimulated targets. Sur face immunoglobulin (sIg) and IL-4R utilize distinct signaling pathways to produce Pas 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-kappa B and depends on new macromole cular synthesis. Proximate mediators for Fas resistance include the known a nti-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 t issue specific. faim is highly evolutionarily conserved, suggesting an impo rtant function throughout phylogeny. Inducible resistance to Fas-mediated a poptosis is speculated to protect antigen-specific B cells during potential ly dangerous interactions with Fast-bearing T cells; the elevated sig-signa ling threshold for inducible Fas resistance in autoreactive, tolerant B cel ls would insure against autoimmunity. However, aberrant acquisition of Fas resistance may allow autoreactive B cells to escape Fas deletion and malign ant lymphocytes to thwart antitumor immunity.