Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 213, Issue 6, Pages 897-911Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151715
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Funding
- Marie Curie Intra-European Fellowship as part of Horizon [H2020-MSCA-IF-2014 660448]
- Fonds Wetenschappelijk Onderzoek PhD fellowship [1102716N]
- Interuniversity Attraction Poles grant (IUAP) from the federal government of Belgium [VII/03]
- Fonds Wetenschappelijk Onderzoek [G.0529.12N, G.0817.13N]
- Geconcerteerde Onderzoeksacties Ghent University [GOA-01GB1013W]
- Belgian Federation for the Study Against Cancer [B/13590]
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Plasmacytoid dendritic cells (DCs [pDCs]) develop from pre-pDCs, whereas two lineages of conventional DCs (cDCs; cDC1s and cDC2s) develop from lineage-committed pre-cDCs. Several transcription factors (TFs) have been implicated in regulating the development of pDCs (E2-2 and Id2) and cDC1s (Irf8, Id2, and Batf3); however, those required for the early commitment of pre-cDCs toward the cDC2 lineage are unknown. Here, we identify the TF zinc finger E box-binding homeobox 2 (Zeb2) to play a crucial role in regulating DC development. Zeb2 was expressed from the pre-pDC and pre-cDC stage onward and highly expressed in mature pDCs and cDC2s. Mice conditionally lacking Zeb2 in CD11c(+) cells had a cell-intrinsic reduction in pDCs and cDC2s, coupled with an increase in cDC1s. Conversely, mice in which CD11c(+) cells overexpressed Zeb2 displayed a reduction in cDC1s. This was accompanied by altered expression of Id2, which was up-regulated in cDC2s and pDCs from conditional knock-out mice. Zeb2 chromatin immunoprecipitation analysis revealed Id2 to be a direct target of Zeb2. Thus, we conclude that Zeb2 regulates commitment to both the cDC2 and pDC lineages through repression of Id2.
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