TY - JOUR
T1 - Single-cell analysis reveals that stochasticity and paracrine signaling control interferon-alpha production by plasmacytoid dendritic cells
AU - Wimmers, Florian
AU - Subedi, Nikita
AU - van Buuringen, Nicole
AU - Heister, Daan
AU - Vivié, Judith
AU - Beeren-Reinieren, Inge
AU - Woestenenk, Rob
AU - Dolstra, Harry
AU - Piruska, Aigars
AU - Jacobs, Joannes F.M.
AU - van Oudenaarden, Alexander
AU - Figdor, Carl G.
AU - Huck, Wilhelm T.S.
AU - de Vries, I. Jolanda M.
AU - Tel, Jurjen
N1 - Funding Information:
The authors want to thank Johannes Textor and Mauro Muraro for supporting the statistical analysis and Michael Valente for enthusiastic discussions. F.W. was supported by a Radboudumc PhD grant. J.T. is supported by NWO-Veni grant 863.130.24 from the Netherlands Organization for Scientific Research and acknowledges generous support by the Eindhoven University of Technology. I.J.M.d.V. received an NWO-Vici award 918.146.55. C.G.F. received the NWO Spinoza award, ERC Advanced Grant PATHFINDER (69019), and Dutch Cancer Society KWO grant 2009–4402. W.T.S.H. acknowledges generous support by the Radboud University and funding from the Ministry of Education, Culture and Science (Gravity program 024.001.035).
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/8/20
Y1 - 2018/8/20
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85052140965
U2 - 10.1038/s41467-018-05784-3
DO - 10.1038/s41467-018-05784-3
M3 - Article
C2 - 30127440
AN - SCOPUS:85052140965
SN - 2041-1723
VL - 9
SP - 1
EP - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3317
ER -