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

Michaël Chopin, Aaron T. Lun, Yifan Zhan, Jaring Schreuder, Hannah Coughlan, Angela D'Amico, Lisa A. Mielke, Francisca F. Almeida, Andrew J. Kueh, Ross A. Dickins, Gabrielle T. Belz, Shalin H. Naik, Andrew M. Lew, Phillipe Bouillet, Marco J. Herold, Gordon K. Smyth, Lynn M. Corcoran, Stephen L. Nutt

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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.

Original languageEnglish
Pages (from-to)77-90.e5
Number of pages19
JournalImmunity
Volume50
Issue number1
DOIs
Publication statusPublished - 15 Jan 2019

Keywords

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

Cite this

Chopin, M., Lun, A. T., Zhan, Y., Schreuder, J., Coughlan, H., D'Amico, A., Mielke, L. A., Almeida, F. F., Kueh, A. J., Dickins, R. A., Belz, G. T., Naik, S. H., Lew, A. M., Bouillet, P., Herold, M. J., Smyth, G. K., Corcoran, L. M., & Nutt, S. L. (2019). Transcription Factor PU.1 Promotes Conventional Dendritic Cell Identity and Function via Induction of Transcriptional Regulator DC-SCRIPT. Immunity, 50(1), 77-90.e5. https://doi.org/10.1016/j.immuni.2018.11.010