Single-cell analysis reveals that stochasticity and paracrine signaling control interferon-alpha production by plasmacytoid dendritic cells

Florian Wimmers, Nikita Subedi, Nicole van Buuringen, Daan Heister, Judith Vivié, Inge Beeren-Reinieren, Rob Woestenenk, Harry Dolstra, Aigars Piruska, Joannes F M Jacobs, Alexander van Oudenaarden, Carl G Figdor, Wilhelm T S Huck, I Jolanda M de Vries, Jurjen Tel

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Type I interferon (IFN) is a key driver of immunity to infections and cancer. Plasmacytoid dendritic cells (pDCs) are uniquely equipped to produce large quantities of type I IFN but the mechanisms that control this process are poorly understood. Here we report on a droplet-based microfluidic platform to investigate type I IFN production in human pDCs at the single-cell level. We show that type I IFN but not TNFα production is limited to a small subpopulation of individually stimulated pDCs and controlled by stochastic gene regulation. Combining single-cell cytokine analysis with single-cell RNA-seq profiling reveals no evidence for a pre-existing subset of type I IFN-producing pDCs. By modulating the droplet microenvironment, we demonstrate that vigorous pDC population responses are driven by a type I IFN amplification loop. Our study highlights the significance of stochastic gene regulation and suggests strategies to dissect the characteristics of immune responses at the single-cell level.

Original languageEnglish
Pages (from-to)3317
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 20 Aug 2018

Keywords

  • Cellular Microenvironment
  • Cross-Priming
  • Dendritic Cells/metabolism
  • Gene Expression Regulation
  • Humans
  • Interferon Type I/biosynthesis
  • Jurkat Cells
  • Paracrine Communication
  • Sequence Analysis, RNA
  • Single-Cell Analysis/methods
  • Stochastic Processes
  • Toll-Like Receptors/metabolism

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