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

• Published in: Immunological reviews 2000-08, Vol.176 (1), p.116-133
• Main Authors: Rothstein, T L, Zhong, X, Schram, B R, Negm, R S, Donohoe, T J, Cabral, D S, Foote, L C, Schneider, T J
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Apoptosis; Apoptosis Regulatory Proteins; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; CD40 antigen; Fas antigen; fas Receptor - metabolism; Humans; Immune Tolerance; Molecular Sequence Data; Proteins - genetics; Proteins - immunology; Receptors, Cell Surface - metabolism; Sequence Homology, Amino Acid; Signal Transduction
• ISSN: 0105-2896; 1600-065X
• DOI: 10.1034/j.1600-065X.2000.00616.x

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 of Fas expression and marked sensitivity to 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-kappaB 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.