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

Florian Wimmers, Nikita Subedi, Nicole Buuringen, Daan Heister, Judith Vivié, Inge Beeren-Reinieren, Rob Woestenenk, Harry Dolstra, Aigars Piruska, Joannes F. M. Jacobs, Alexander Oudenaarden, Carl G. Figdor, Wilhelm T. S. Huck, I. Jolanda M. Vries and Jurjen Tel ()
Additional contact information
Florian Wimmers: Radboud University Medical Center
Nikita Subedi: Eindhoven University of Technology
Nicole Buuringen: Radboud University Medical Center
Daan Heister: Radboud University Medical Center
Judith Vivié: Hubrecht Institute - KNAW and University Medical Center Utrecht
Inge Beeren-Reinieren: Radboud University Medical Center
Rob Woestenenk: Radboud University Medical Center
Harry Dolstra: Radboud University Medical Center
Aigars Piruska: Radboud University
Joannes F. M. Jacobs: Radboud University Medical Center
Alexander Oudenaarden: Hubrecht Institute - KNAW and University Medical Center Utrecht
Carl G. Figdor: Radboud University Medical Center
Wilhelm T. S. Huck: Radboud University
I. Jolanda M. Vries: Radboud University Medical Center
Jurjen Tel: Radboud University Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05784-3

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