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Bhushal S, Wolfsmüller M, Selvakumar TA, et al. Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells. Front Immunol. 2017;8:671doi: 10.3389/fimmu.2017.00671.
Bhushal, S., Wolfsmüller, M., Selvakumar, T. A., Kemper, L., Wirth, D., Hornef, M. W., Hauser, H., & Köster, M. (2017). Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells. Frontiers in immunology, 8671. https://doi.org/10.3389/fimmu.2017.00671
Bhushal, Sudeep, et al. "Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells." Frontiers in immunology vol. 8 (2017): 671. doi: https://doi.org/10.3389/fimmu.2017.00671
Bhushal S, Wolfsmüller M, Selvakumar TA, Kemper L, Wirth D, Hornef MW, Hauser H, Köster M. Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells. Front Immunol. 2017 Jun 12;8:671. doi: 10.3389/fimmu.2017.00671. eCollection 2017. PMID: 28659914; PMCID: PMC5467006.
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Front Immunol. 2017 Jun 12;8:671. doi: 10.3389/fimmu.2017.00671. eCollection 2017.

Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells.

Frontiers in immunology

Sudeep Bhushal, Markus Wolfsmüller, Tharini A Selvakumar, Lucas Kemper, Dagmar Wirth, Mathias W Hornef, Hansjörg Hauser, Mario Köster

Affiliations

  1. Research Group Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany.
  2. Institute for Medical Microbiology, RWTH Aachen University Hospital, Aachen, Germany.

PMID: 28659914 PMCID: PMC5467006 DOI: 10.3389/fimmu.2017.00671

Abstract

Type I and type III interferons (IFNs) are crucial components of the first-line antiviral host response. While specific receptors for both IFN types exist, intracellular signaling shares the same Jak-STAT pathway. Due to its receptor expression, IFN-λ responsiveness is restricted mainly to epithelial cells. Here, we display IFN-stimulated gene induction at the single cell level to comparatively analyze the activities of both IFN types in intestinal epithelial cells and mini-gut organoids. Initially, we noticed that the response to both types of IFNs at low concentrations is based on a single cell decision-making determining the total cell intrinsic antiviral activity. We identified histone deacetylase (HDAC) activity as a crucial restriction factor controlling the cell frequency of IFN-stimulated gene (ISG) induction upon IFN-λ but not IFN-β stimulation. Consistently, HDAC blockade confers antiviral activity to an elsewise non-responding subpopulation. Second, in contrast to the type I IFN system, polarization of intestinal epithelial cells strongly enhances their ability to respond to IFN-λ signaling and raises the kinetics of gene induction. Finally, we show that ISG induction in mini-gut organoids by low amounts of IFN is characterized by a scattered heterogeneous responsiveness of the epithelial cells and HDAC activity fine-tunes exclusively IFN-λ activity. This study provides a comprehensive description of the differential response to type I and type III IFNs and demonstrates that cell polarization in gut epithelial cells specifically increases IFN-λ activity.

Keywords: cell polarization; epithelial cell line; heterogeneous gene expression; interferon-lambda; small intestinal organoids

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