title: Essential role for the transcription factor Bhlhe41 in regulating the development, self-renewal and BCR repertoire of B-1a cells.
abstract: Innate-like B-1a cells provide a first line of defense against pathogens, yet little is known about their transcriptional control. Here we identified an essential role for the transcription factor Bhlhe41, with a lesser contribution by Bhlhe40, in controlling B-1a cell differentiation. Bhlhe41-/-Bhlhe40-/-B-1a cells were present at much lower abundance than were their wild-type counterparts. Mutant B-1a cells exhibited an abnormal cell-surface phenotype and altered B cell receptor (BCR) repertoire exemplified by loss of the phosphatidylcholine-specific VH12Vκ4 BCR. Expression of a pre-rearranged VH12Vκ4 BCR failed to 'rescue' the mutant phenotype and revealed enhanced proliferation accompanied by increased cell death. Bhlhe41 directly repressed the expression of cell-cycle regulators and inhibitors of BCR signaling while enabling pro-survival cytokine signaling. Thus, Bhlhe41 controls the development, BCR repertoire and self-renewal of B-1a cells.
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria.
authors.forename: Taras
authors.initials: T
authors.lastname: Kreslavsky
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria.
authors.forename: Bojan
authors.initials: B
authors.lastname: Vilagos
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tagoh
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria.
authors.forename: Daniela Kostanova
authors.initials: DK
authors.lastname: Poliakova
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria.
authors.forename: Tanja A
authors.initials: TA
authors.lastname: Schwickert
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria.
authors.forename: Miriam
authors.initials: M
authors.lastname: Wöhner
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Jaritz
authors.affiliation: Department of Molecular Immunology, Helmholtz Center for Infection Research, Braunschweig, and Institute of Immunology, Medical School, Hannover, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Reshma
authors.initials: R
authors.lastname: Taneja
authors.affiliation: Department of Psychiatry, Ludwig Maximillian University of Munich, Munich, Germany.
authors.forename: Moritz J
authors.initials: MJ
authors.lastname: Rossner
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D015415:Biomarkers; D002454:Cell Differentiation / Q000235:genetics; D000066673:Cell Self Renewal / Q000235:genetics; D005786:Gene Expression Regulation; D005803:Genes, Immunoglobulin; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D059372:Nucleotide Motifs; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D056510:Position-Specific Scoring Matrices; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D011947:Receptors, Antigen, B-Cell; D012097:Repressor Proteins