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

2.50
Hdl Handle:
http://hdl.handle.net/10033/621068
Title:
Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells.
Authors:
Bhushal, Sudeep; Wolfsmüller, Markus; Selvakumar, Tharini A; Kemper, Lucas; Wirth, Dagmar; Hornef, Mathias W; Hauser, Hansjörg; Köster, Mario
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.
Affiliation:
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
Cell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells. 2017, 8:671 Front Immunol
Journal:
Frontiers in immunology
Issue Date:
2017
URI:
http://hdl.handle.net/10033/621068
DOI:
10.3389/fimmu.2017.00671
PubMed ID:
28659914
Type:
Article
Language:
en
ISSN:
1664-3224
Appears in Collections:
publications of the research group modell systems for infections and immunity (MSYS); publications of the scientific administration (GFW)

Full metadata record

DC FieldValue Language
dc.contributor.authorBhushal, Sudeepen
dc.contributor.authorWolfsmüller, Markusen
dc.contributor.authorSelvakumar, Tharini Aen
dc.contributor.authorKemper, Lucasen
dc.contributor.authorWirth, Dagmaren
dc.contributor.authorHornef, Mathias Wen
dc.contributor.authorHauser, Hansjörgen
dc.contributor.authorKöster, Marioen
dc.date.accessioned2017-08-22T12:59:08Z-
dc.date.available2017-08-22T12:59:08Z-
dc.date.issued2017-
dc.identifier.citationCell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells. 2017, 8:671 Front Immunolen
dc.identifier.issn1664-3224-
dc.identifier.pmid28659914-
dc.identifier.doi10.3389/fimmu.2017.00671-
dc.identifier.urihttp://hdl.handle.net/10033/621068-
dc.description.abstractType 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.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleCell Polarization and Epigenetic Status Shape the Heterogeneous Response to Type III Interferons in Intestinal Epithelial Cells.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalFrontiers in immunologyen

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