title: Rapid CD40-mediated rescue from CD95-induced apoptosis requires TNFR-associated factor-6 and PI3K.
abstract: The activation molecule CD40 and the death receptor CD95/Fas play important roles in regulating B cells so that effective antimicrobial immunity occurs without autoimmunity. CD40 signaling increases CD95 expression, sensitizing cells to apoptosis, but sustained CD40 signals rescue B cells from CD95 killing. Here we describe a mechanism of early CD40-mediated rescue from CD95-induced apoptosis in B cells. Maximal rescue was achieved when CD40 signals were given within 1-2 h of initiating CD95 apoptosis. CD40 signaling did not block association of Fas-associated death domain-containing protein with CD95, but decreased CD95-induced activation of caspases 3 and 8. Rapid CD40 rescue did not require NF-kappaB activation and was independent of de novo protein synthesis, but was dependent upon active PI3 K. Signaling via a CD40 mutant that does not bind TNFR-associated factor (TRAF)1, TRAF2, and TRAF3 rescued B cells from CD95-induced apoptosis. TRAF1/2/3-independent rescue was confirmed in B cell lines made deficient in these TRAF molecules by gene targeting. In contrast, CD40 rescue was completely abrogated in TRAF6-deficient B cells, which showed reduced activation of Akt in response to CD40 engagement. These results reveal a new rapid mechanism to balance B cell activation and apoptosis.
authors.affiliation: Medical Scientist Training Program and Immunology Graduate Program, University of Iowa and Veterans Affairs Medical Center, Iowa City 52245, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Benson
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Hostager
authors.forename: Gail A
authors.initials: GA
authors.lastname: Bishop
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D020169:Caspases / Q000276:immunology; D002460:Cell Line; D004789:Enzyme Activation / Q000276:immunology; D015151:Immunoblotting; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology* / Q000378:metabolism; D047990:TNF Receptor-Associated Factor 1 / Q000172:deficiency / Q000276:immunology; D047992:TNF Receptor-Associated Factor 2 / Q000172:deficiency / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3 / Q000172:deficiency / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000276:immunology; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D018124:Receptors, Tumor Necrosis Factor; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D048029:TNF Receptor-Associated Factor 6; D019014:fas Receptor; D019869:Phosphatidylinositol 3-Kinases; D020169:Caspases