Non-overlapping Fas- and BCL-2-regulated death pathways in IgG2a(b)-producing B cells.
Using perforin (Pfp)- and/or Fas-dependent cytotoxic pathways, T splenocytes from Igh(a/a) mice are able in vivo to totally and chronically eliminate congenic Igh(b/b) B cells committed to IgG2a(b) production. This phenomenon leads to a characteristic absence of serum IgG2a(b) expression (IgG2a(b) allotype suppression) in, for instance, histocompatible Igh(a/b) or Igh(b/b) mice, having neonatally received such T cells. Because the study of the protective role of BCL-2 oncoprotein against Fas-mediated cell death has generated contradictory findings, we examined the possible impact of constitutive overexpression of transgenic human BCL-2 protein in Igh(b/b) B cells when the latter were exposed in vivo exclusively with the Fas-dependent, anti-IgG2a(b) T cell activity of Igh(a/a) Pfp(0/0) mice. We observed that, despite high intracellular expression of functional transgenic BCL-2 and no up-regulation of the principal BCL-2 inhibitors in whole Igh(b/b) B cells, total, chronic and specific IgG2a(b) suppression was exerted by Igh(a/a) Pfp(0/0) cytotoxic T cells. These data show that, in this model of negative regulation of Ig production, Fas- and BCL-2-regulated mechanisms belong to non-overlapping death pathways at the level of IgG2a(b)-producing B cells, targets of Igh(a/a) T cell-mediated cytotoxicity. Thus, in these mature B cells, the Fas signaling-directly operating via caspase 8-does not involve a mitochondria-dependent pathway regulated by BCL-2.
Majlessi
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L
Unité d'Immunophysiologie Moléculaire, Institut Pasteur, 25 rue du Docteur-Roux, 75724 Paris Cedex 15, France.
Bordenave
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G
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000145:classification / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*
D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D019014:fas Receptor