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Immunity. 2019 Jan 15;50(1):77-90.e5. doi: 10.1016/j.immuni.2018.11.010. Epub 2019 Jan 2.

Transcription Factor PU.1 Promotes Conventional Dendritic Cell Identity and Function via Induction of Transcriptional Regulator DC-SCRIPT.

Author information

1
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: chopin@wehi.edu.au.
2
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
3
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia.
4
Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia.
5
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC 3010, Australia.
6
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; School of Mathematics and Statistics, University of Melbourne, Parkville, VIC 3010, Australia.
7
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: nutt@wehi.edu.au.

Abstract

Dendritic cells (DCs) are can be broadly divided into conventional (cDC) and plasmacytoid (pDC) subsets. Despite the importance of this lineage diversity, its genetic basis is not fully understood. We found that conditional ablation of the Ets-family transcription factor PU.1 in DC-restricted progenitors led to increased pDC production at the expense of cDCs. PU.1 controlled many of the cardinal functions of DCs, such as antigen presentation by cDCs and type I interferon production by pDCs. Conditional ablation of PU.1 de-repressed the pDC transcriptional signature in cDCs. The combination of genome-wide mapping of PU.1 binding and gene expression analysis revealed a key role for PU.1 in maintaining cDC identity through the induction of the transcriptional regulator DC-SCRIPT. PU.1 activated DC-SCRIPT expression, which in turn promoted cDC formation, particularly of cDC1s, and repressed pDC development. Thus, cDC identity is regulated by a transcriptional node requiring PU.1 and DC-SCRIPT.

KEYWORDS:

DC-SCRIPT; PU.1; cell differentiation; dendritic cell; plasmacytoid dendritic cell; transcription factor

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