An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development

Nat Immunol. 2019 Sep;20(9):1174-1185. doi: 10.1038/s41590-019-0449-3. Epub 2019 Aug 12.


Classical type 1 dendritic cells (cDC1s) are required for antiviral and antitumor immunity, which necessitates an understanding of their development. Development of the cDC1 progenitor requires an E-protein-dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor Irf8 (+41-kb Irf8 enhancer), but its maturation instead requires the Batf3-dependent +32-kb Irf8 enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as Nfil3, Id2 and Zeb2. Genetic epistasis among these factors revealed that Nfil3 expression is required for the transition from Zeb2hi and Id2lo CDPs to Zeb2lo and Id2hi CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E-protein activity to exclude plasmacytoid dendritic cell potential and explains the switch in Irf8 enhancer usage during cDC1 development.

Publication types

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

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Dendritic Cells / cytology*
  • Enhancer Elements, Genetic / genetics*
  • Gene Expression Regulation, Developmental / genetics
  • Inhibitor of Differentiation Protein 2 / metabolism*
  • Interferon Regulatory Factors / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Repressor Proteins / metabolism
  • Stem Cells / cytology
  • Zinc Finger E-box Binding Homeobox 2 / metabolism*


  • Basic-Leucine Zipper Transcription Factors
  • Idb2 protein, mouse
  • Inhibitor of Differentiation Protein 2
  • Interferon Regulatory Factors
  • Nfil3 protein, mouse
  • Repressor Proteins
  • SNFT protein, mouse
  • ZEB2 protein, mouse
  • Zinc Finger E-box Binding Homeobox 2
  • interferon regulatory factor-8