Batf3 Maintains Autoactivation of Irf8 for Commitment of a CD8α(+) Conventional DC Clonogenic Progenitor

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / immunology*
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • CD24 Antigen / immunology
  • CD24 Antigen / metabolism
  • CD8 Antigens / immunology
  • CD8 Antigens / metabolism
  • Cells, Cultured
  • Clone Cells / immunology
  • Clone Cells / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Flow Cytometry
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / immunology*
  • Interferon Regulatory Factors / metabolism
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Protein Binding
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / immunology*
  • Repressor Proteins / metabolism
  • Sequence Homology, Nucleic Acid
  • Stem Cells / immunology*
  • Stem Cells / metabolism
  • Transcriptome / genetics
  • Transcriptome / immunology

Substances

  • Basic-Leucine Zipper Transcription Factors
  • CD24 Antigen
  • CD8 Antigens
  • CD8alpha antigen
  • Interferon Regulatory Factors
  • Ptpns1 protein, mouse
  • Receptors, Immunologic
  • Repressor Proteins
  • SNFT protein, mouse
  • interferon regulatory factor-8

Associated data

  • GEO/GSE66565