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Nat Commun. 2018 Aug 20;9(1):3317. doi: 10.1038/s41467-018-05784-3.

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

Author information

1
Department of Tumor Immunology, Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.
2
Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, 94305, CA, USA.
3
Department of Biomedical Engineering, Laboratory of Immunoengineering, Eindhoven University of Technology, Eindhoven, 5612 AZ, The Netherlands.
4
Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, 5612 AZ, The Netherlands.
5
Hubrecht Institute - KNAW and University Medical Center Utrecht, Utrecht, 3584 CT, The Netherlands.
6
Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.
7
Department of Physical Organic Chemistry, Institute for Molecules and Materials, Radboud University, Nijmegen, 6525 HP, The Netherlands.
8
Department of Laboratory Medicine, Laboratory Medical Immunology, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands.
9
Department of Tumor Immunology, Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6525 GA, The Netherlands. J.Tel@tue.nl.
10
Department of Biomedical Engineering, Laboratory of Immunoengineering, Eindhoven University of Technology, Eindhoven, 5612 AZ, The Netherlands. J.Tel@tue.nl.
11
Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, 5612 AZ, The Netherlands. J.Tel@tue.nl.

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.

PMID:
30127440
PMCID:
PMC6102223
DOI:
10.1038/s41467-018-05784-3
[Indexed for MEDLINE]
Free PMC Article

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