Dendritic cell fate is determined by BCL11A

Gregory C. Ippolito, Joseph D. Dekker, Yui Hsi Wang, Bum Kyu Lee, Arthur L. Shaffer, Jian Lin, Jason K. Wall, Baeck Seung Lee, Louis M. Staudt, Yong Jun Liu, Vishwanath R. Iyer, Haley O. Tucker

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E998-E1006
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number11
DOIs
StatePublished - Mar 18 2014

ASJC Scopus subject areas

  • General

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