title: Increased ID2 levels in adult precursor B cells as compared with children is associated with impaired Ig locus contraction and decreased bone marrow output.
abstract: Precursor B cell production from bone marrow in mice and humans declines with age. Because the mechanisms behind are still unknown, we studied five precursor B cell subsets (ProB, PreBI, PreBII large, PreBII small, immature B) and their differentiation-stage characteristic gene expression profiles in healthy individual toddlers and middle-aged adults. Notably, the composition of the precursor B cell compartment did not change with age. The expression levels of several transcripts encoding V(D)J recombination factors were decreased in adults as compared with children: RAG1 expression was significantly reduced in ProB cells, and DNA-PKcs, Ku80, and XRCC4 were decreased in PreBI cells. In contrast, TdT was 3-fold upregulated in immature B cells of adults. Still, N-nucleotides, P-nucleotides, and deletions were similar for IGH and IGK junctions between children and adults. PreBII large cells in adults, but not in children, showed highly upregulated expression of the differentiation inhibitor, inhibitor of DNA binding 2 (ID2), in absence of changes in expression of the ID2-binding partner E2A. Further, we identified impaired Ig locus contraction in adult precursor B cells as a likely mechanism by which ID2-mediated blocking of E2A function results in reduced bone marrow B cell output in adults. The reduced B cell production was not compensated by increased proliferation in adult immature B cells, despite increased Ki67 expression. These findings demonstrate distinct regulatory mechanisms in B cell differentiation between adults and children with a central role for transcriptional regulation of ID2.
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, 0407 Oslo, Norway. kristin.jensen@medisin.uio.no
authors.forename: Kristin
authors.initials: K
authors.lastname: Jensen
authors.forename: Magdalena B
authors.initials: MB
authors.lastname: Rother
authors.forename: Berit Sletbakk
authors.initials: BS
authors.lastname: Brusletto
authors.forename: Ole K
authors.initials: OK
authors.lastname: Olstad
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Dalsbotten Aass
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
authors.forename: Peter
authors.initials: P
authors.lastname: Kierulf
authors.forename: Kaare M
authors.initials: KM
authors.lastname: Gautvik
mesh_terms: D034961:Antigens, Nuclear / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D000072200:Ku Autoantigen; D018655:Lymphocyte Count; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation; D060152:V(D)J Recombination / Q000235:genetics
chemical_list: D034961:Antigens, Nuclear; D051792:Basic Helix-Loop-Helix Proteins; D004253:DNA Nucleotidylexotransferase; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051797:Inhibitor of Differentiation Protein 2; D019394:Ki-67 Antigen; D000072200:Ku Autoantigen; D009687:Nuclear Proteins; D012333:RNA, Messenger; C497450:ID2 protein, human; C407909:TCF3 protein, human; C101467:XRCC4 protein, human; C064658:RAG-1 protein; C497263:PRKDC protein, human; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse