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Nat Immunol. 2015 Jul;16(7):708-17. doi: 10.1038/ni.3197. Epub 2015 Jun 8.

Batf3 maintains autoactivation of Irf8 for commitment of a CD8α(+) conventional DC clonogenic progenitor.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
2
Department of Medicine A, Hematology and Oncology, University of Muenster, Muenster, Germany.
3
1] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Department of Biomedicine, University of Basel, Basel, Switzerland.
4
Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
5
Institute of Molecular Tumor Biology, University of Münster, Münster, Germany.
6
1] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri, USA.

Abstract

The transcription factors Batf3 and IRF8 are required for the development of CD8α(+) conventional dendritic cells (cDCs), but the basis for their actions has remained unclear. Here we identified two progenitor cells positive for the transcription factor Zbtb46 that separately generated CD8α(+) cDCs and CD4(+) cDCs and arose directly from the common DC progenitor (CDP). Irf8 expression in CDPs required prior autoactivation of Irf8 that was dependent on the transcription factor PU.1. Specification of the clonogenic progenitor of CD8α(+) cDCs (the pre-CD8 DC) required IRF8 but not Batf3. However, after specification of pre-CD8 DCs, autoactivation of Irf8 became Batf3 dependent at a CD8α(+) cDC-specific enhancer with multiple transcription factor AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3(-/-) mice that were specified toward development into pre-CD8 DCs failed to complete their development into CD8α(+) cDCs due to decay of Irf8 autoactivation and diverted to the CD4(+) cDC lineage.

Comment in

PMID:
26054719
PMCID:
PMC4507574
DOI:
10.1038/ni.3197
[Indexed for MEDLINE]
Free PMC Article

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