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Basal IFNλ2/3, but not IFNλ1, signaling is sufficient to control virus infection in intestinal epithelial cells

ABSTRACT: Interferon-lambdas (IFNλs) serve as critical mediators of antiviral defense at mucosal surfaces. Beyond their established role in regulating innate immune responses during infection, recent evidence demonstrates that IFNλs are constitutively expressed in pathogen-free environments, termed "basal" IFN expression. While intestinal epithelial cells constitutively express all basal IFNλ subtypes (IFNλ1, IFNλ2, and IFNλ3), their individual contributions to antiviral immunity remain poorly defined. Here, we systematically investigate the distinct roles of IFNλ1 and IFNλ2/3 in regulating intrinsic antiviral immunity using human intestinal epithelial T84 cells. Through genetic depletion of IFNλ1 or IFNλ2/3, we show that basal IFNλ2/3, but not IFNλ1, is essential for restricting replication and spread of diverse viruses, including vesicular stomatitis virus (VSV), mammalian orthoreovirus (MRV), rotavirus (RV), and vaccinia virus (VV). Transcriptomic profiling revealed that IFNλ2/3 selectively controls the basal expression of interferon-stimulated genes (ISGs), including key antiviral effectors and components of the IFN signaling machinery (e.g., STAT1, STAT2, IRF9). Loss of IFNλ2/3 reduced total STAT1 protein levels and blunted responsiveness to exogenous IFNλ, indicating compromised interferon signaling capacity. Furthermore, basal IFNλ2/3 was required for activating paracrine JAK/STAT signaling and ISG induction in neighboring bystander cells, thereby amplifying antiviral protection across the epithelial layer. These findings reveal a functional hierarchy among IFNλ subtypes and establish IFNλ2/3 as the dominant, non-redundant regulators of epithelial immune readiness. Our study provides the first comprehensive analysis of basal IFNλ subtype functions in the gut epithelium and underscores the central role of basal IFNλ2/3 in maintaining mucosal antiviral defense.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296527 | GEO | 2026/01/04

REPOSITORIES: GEO

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Project description:Begitt2014 - STAT1 cooperative DNA binding - double GAS polymer model The importance of STAT1-cooperative DNA binding in type 1 and type 2 interferon signalling has been studies using experimental and modelling approaches. The authors have developed two ODE models to describe STAT1 binding to short promoter regions of DNA, namely "single GAS polymer model" and "double GAS polymer model" considering binding to single or double GAS sites, respectively. The length of DNA in the single GAS model was three sites and four sites in double GAS model. This model correspond to the "double GAS polymer model". This model is described in the article: STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling. Begitt A, Droescher M, Meyer T, Schmid CD, Baker M, Antunes F, Owen MR, Naumann R, Decker T, Vinkemeier U Nat Immunol. 2014 Feb;15(2):168-76. Abstract: STAT1 is an indispensable component of a heterotrimer (ISGF3) and a STAT1 homodimer (GAF) that function as transcription regulators in type 1 and type 2 interferon signaling, respectively. To investigate the importance of STAT1-cooperative DNA binding, we generated gene-targeted mice expressing cooperativity-deficient STAT1 with alanine substituted for Phe77. Neither ISGF3 nor GAF bound DNA cooperatively in the STAT1F77A mouse strain, but type 1 and type 2 interferon responses were affected differently. Type 2 interferon-mediated transcription and antibacterial immunity essentially disappeared owing to defective promoter recruitment of GAF. In contrast, STAT1 recruitment to ISGF3 binding sites and type 1 interferon-dependent responses, including antiviral protection, remained intact. We conclude that STAT1 cooperativity is essential for its biological activity and underlies the cellular responses to type 2, but not type 1 interferon. This model is hosted on BioModels Database and identified by: BIOMD0000000501 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Begitt2014 - STAT1 cooperative DNA binding - single GAS polymer model The importance of STAT1-cooperative DNA binding in type 1 and type 2 interferon signalling has been studies using experimental and modelling approaches. The authors have developed two ODE models to describe STAT1 binding to short promoter regions of DNA, namely "single GAS polymer model" and "double GAS polymer model" considering binding to single or double GAS sites, respectively. The length of DNA in the single GAS model was three sites and four sites in double GAS model. This model correspond to the "single GAS polymer model". This model is described in the article: STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling. Begitt A, Droescher M, Meyer T, Schmid CD, Baker M, Antunes F, Owen MR, Naumann R, Decker T, Vinkemeier U Nat Immunol. 2014 Feb;15(2):168-76. Abstract: STAT1 is an indispensable component of a heterotrimer (ISGF3) and a STAT1 homodimer (GAF) that function as transcription regulators in type 1 and type 2 interferon signaling, respectively. To investigate the importance of STAT1-cooperative DNA binding, we generated gene-targeted mice expressing cooperativity-deficient STAT1 with alanine substituted for Phe77. Neither ISGF3 nor GAF bound DNA cooperatively in the STAT1F77A mouse strain, but type 1 and type 2 interferon responses were affected differently. Type 2 interferon-mediated transcription and antibacterial immunity essentially disappeared owing to defective promoter recruitment of GAF. In contrast, STAT1 recruitment to ISGF3 binding sites and type 1 interferon-dependent responses, including antiviral protection, remained intact. We conclude that STAT1 cooperativity is essential for its biological activity and underlies the cellular responses to type 2, but not type 1 interferon. This model is hosted on BioModels Database and identified by: BIOMD0000000500 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Basal IFNλ2/3, but not IFNλ1, signaling is sufficient to control virus infection in intestinal epithelial cells

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