title: Combined loss of the BH3-only proteins Bim and Bmf restores B-cell development and function in TACI-Ig transgenic mice.
abstract: Terminal differentiation of B cells depends on two interconnected survival pathways, elicited by the B-cell receptor (BCR) and the BAFF receptor (BAFF-R), respectively. Loss of either signaling pathway arrests B-cell development. Although BCR-dependent survival depends mainly on the activation of the v-AKT murine thymoma viral oncogene homolog 1 (AKT)/PI3-kinase network, BAFF/BAFF-R-mediated survival engages non-canonical NF-κB signaling as well as MAPK/extracellular-signal regulated kinase and AKT/PI3-kinase modules to allow proper B-cell development. Plasma cell survival, however, is independent of BAFF-R and regulated by APRIL that signals NF-κB activation via alternative receptors, that is, transmembrane activator and CAML interactor (TACI) or B-cell maturation (BCMA). All these complex signaling events are believed to secure survival by increased expression of anti-apoptotic B-cell lymphoma 2 (Bcl2) family proteins in developing and mature B cells. Curiously, how lack of BAFF- or APRIL-mediated signaling triggers B-cell apoptosis remains largely unexplored. Here, we show that two pro-apoptotic members of the 'Bcl2 homology domain 3-only' subgroup of the Bcl2 family, Bcl2 interacting mediator of cell death (Bim) and Bcl2 modifying factor (Bmf), mediate apoptosis in the context of TACI-Ig overexpression that effectively neutralizes BAFF as well as APRIL. Surprisingly, although Bcl2 overexpression triggers B-cell hyperplasia exceeding the one observed in Bim(-/-)Bmf(-/-) mice, Bcl2 transgenic B cells remain susceptible to the effects of TACI-Ig expression in vivo, leading to ameliorated pathology in Vav-Bcl2 transgenic mice. Together, our findings shed new light on the molecular machinery restricting B-cell survival during development, normal homeostasis and under pathological conditions. Our data further suggest that Bcl2 antagonists might improve the potency of BAFF/APRIL-depletion strategies in B-cell-driven pathologies.
authors.affiliation: 1] Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria [2] Institute for Legal Medicine, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Woess
authors.affiliation: Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Tuzlak
authors.affiliation: Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: V
authors.initials: V
authors.lastname: Labi
authors.affiliation: 1] Institute for Pathology, Medical University Innsbruck, Innsbruck, Austria [2] Institute of Surgical Pathology, University Hospital, Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Drach
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Divsion of Pediatric Hematology and Oncology, University Hospital of Freiburg, Freiburg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Bertele
authors.affiliation: Department of Biochemistry, University of Lausanne, Lausanne, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Schneider
authors.affiliation: Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Villunger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C474007:Bax protein (53-86); D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C435486:Bmf protein, mouse; D008565:Membrane Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C524618:TACI receptor-IgG Fc fragment fusion protein