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.
Highlights
The innate defense against viral infection in mammals is based on the coordinated action of type I and type III interferons (IFNs), which are produced by virus-infected and bystander cells [1,2,3]
In order to investigate the differences in type I and III IFNmediated signaling, we used a recently described intestinal epithelial cell line (IEC) that was derived from a transgenic mouse expressing a firefly luciferase reporter under the transcriptional control of the IFN-dependent mouse Myxovirus resistance gene 2 (Mx2) promoter [21]
IFN-stimulated gene expression was normalized to β-Actin (n = 3, mean ± SEM). *P ≤ 0.05 by Mann–Whitney U test. (C) IECs were stimulated with 20 ng/ml IFN-λ3 in the absence or presence of 750 μM valproic acid (VPA) for 20 h
Summary
The innate defense against viral infection in mammals is based on the coordinated action of type I and type III interferons (IFNs), which are produced by virus-infected and bystander cells [1,2,3]. IFNs induce antiviral mechanisms within virus-infected and uninfected cells and contribute to the adaptive immune responses against viral pathogens [4, 5] Both IFN types reprogram gene expression through the same signal transduction pathway involving the formation of the ternary ISGF3 complex, composed of STAT1, STAT2, and IRF9 [6]. Whereas all type I IFNs utilize a heterodimeric receptor complex composed of IFN-αR1 and IFN-αR2 subunits, type III IFNs engage the IFN-λR1 ( known as IL28R) and IL10R2 receptor chains for signaling [2, 3]. Because most pathogens enter the host through mucosal surfaces, the IFN-λbased antiviral response is the determining factor to establish the first line of defense against invading pathogens [12,13,14]
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