title: Dendritic cell fate is determined by BCL11A.
abstract: The plasmacytoid dendritic cell (pDC) is vital to the coordinated action of innate and adaptive immunity. pDC development has not been unequivocally traced, nor has its transcriptional regulatory network been fully clarified. Here we confirm an essential requirement for the BCL11A transcription factor in fetal pDC development, and demonstrate this lineage-specific requirement in the adult organism. Furthermore, we identify BCL11A gene targets and provide a molecular mechanism for its action in pDC commitment. Embryonic germ-line deletion of Bcl11a revealed an absolute cellular, molecular, and functional absence of pDCs in fetal mice. In adults, deletion of Bcl11a in hematopoietic stem cells resulted in perturbed yet continued generation of progenitors, loss of downstream pDC and B-cell lineages, and persisting myeloid, conventional dendritic, and T-cell lineages. Challenge with virus resulted in a marked reduction of antiviral response in conditionally deleted adults. Genome-wide analyses of BCL11A DNA binding and expression revealed that BCL11A regulates transcription of E2-2 and other pDC differentiation modulators, including ID2 and MTG16. Our results identify BCL11A as an essential, lineage-specific factor that regulates pDC development, supporting a model wherein differentiation into pDCs represents a primed "default" pathway for common dendritic cell progenitors.
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Ippolito
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Dekker
authors.forename: Yui-Hsi
authors.initials: YH
authors.lastname: Wang
authors.forename: Bum-Kyu
authors.initials: BK
authors.lastname: Lee
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Shaffer
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Jason K
authors.initials: JK
authors.lastname: Wall
authors.forename: Baeck-Seung
authors.initials: BS
authors.lastname: Lee
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Vishwanath R
authors.initials: VR
authors.lastname: Iyer
authors.forename: Haley O
authors.initials: HO
authors.lastname: Tucker
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology*; D053263:Gene Regulatory Networks / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C407733:Bcl11a protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins