Single-cell analysis reveals that stochasticity and paracrine signaling control interferon-alpha production by plasmacytoid dendritic cells
Open accessAbstract
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.
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The type I IFN response can be heterogeneous: it depends on the reacting cell's state, is at least partly stochastic, varies among cell types and microenvironments, and shows interindividual heterogeneity in amplitude and kinetics.
“Importantly, the type I IFN response can be rather heterogeneous. Depending on the state of the reacting cell (e.g., with respect to its metabolic or general activation state) (Talemi and Höfer, 2018), it is at least in part stochastic (Rand et al., 2012; Wimmers et al., 2018), it varies among different cell types and microenvironments, and it shows interindividual heterogeneity concerning the”
From COVID-19 and the human innate immune system (2021) · cites this paper as Wimmers et al., 2018
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A Pipette-Tip Based Method for Seeding Cells to Droplet Microfluidic Platforms
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- Authors
- Wimmers, F., Subedi, N., van Buuringen, N., Heister, D., Vivié, J., Beeren-Reinieren, I., Woestenenk, R., Dolstra, H., Piruska, A., Jacobs, J. F. M., van Oudenaarden, A., Figdor, C. G., Huck, W. T. S., de Vries, I. J. M., & Tel, J.
- Affiliations
- Radboud University Medical Center (NL)
- Eindhoven University of Technology (NL)
- University Medical Center Utrecht (NL)
- Radboud University Nijmegen (NL)
- Corresponding author
- Tel, Jurjen
- ORCID
- Venue
- Nature Communications
- Published
- 2018-08-20
- Volume
- 9
- Issue
- 1
- Pages
- 3317-3317
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6102223
- OpenAlex
- W2885999695
- Cited by
- 150
- References
- 53
- Citations by year
- 2026: 3 · 2025: 17 · 2024: 11 · 2023: 26 · 2022: 21 · 2021: 24 · 2020: 20 · 2019: 26 · 2018: 2
- FWCI
- 7.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- TU/e Research Portal (acceptedVersion, other-oa)
- TU/e Research Portal (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- TU/e Research Portal (submittedVersion, other-oa)
- Funders
- Radboud Universitair Medisch Centrum (PhD grant)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (863.130.24, Spinoza Award, Spinoza award)
- Generous support by the Eindhoven University of Technology
- Ministerie van Onderwijs, Cultuur en Wetenschap (024.001.035)
- generous support by the Radboud University
- KWF Kankerbestrijding (2009-4402)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- plasmacytoid dendritic cells, type I interferon, interferon-alpha production, stochastic gene regulation, paracrine signaling, droplet microfluidics, single-cell RNA sequencing, TNF-α, immune response heterogeneity
- MeSH terms
- Dendritic Cells, Gene Expression Regulation, Humans, Interferon Type I, Stochastic Processes, Sequence Analysis, RNA, Jurkat Cells, Paracrine Communication, Cross-Priming, Toll-Like Receptors, Single-Cell Analysis, Cellular Microenvironment
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