# Conditional Stat2 Knockout Mice as a Platform for Modeling Human Diseases

## TL;DR

This paper introduces a conditional Stat2 knockout mouse model to study the role of STAT2 in immune responses and disease processes.

## Contribution

The study expands the utility of the conditional Stat2 KO mouse by validating tissue-specific models and demonstrating their functional relevance.

## Key findings

- Conditional Stat2 deletion disrupts IFN-I signaling in splenocytes and antitumor responses in vivo.
- Lung fibroblasts from Stat2 KO mice show impaired antiviral responses to IFN-β.
- Tissue-specific Cre models allow selective ablation of STAT2 without affecting non-target tissues.

## Abstract

Signal transducer and activator of transcription 2 (STAT2) is a key component of the type I interferon (IFN-I/III) signaling pathway, which is pivotal in host defense against cancer and viral infections and in shaping immune responses. Building on our previously reported conditional Stat2 knockout (KO) mouse, we expand its utility by validating additional tissue-specific models and exploring novel functional contexts. Mice carrying loxP-flanked Stat2 alleles were crossed with CMV-Cre, Cdx2-Cre or CD11c-Cre mice. Deletion of STAT2 was validated by PCR genotyping and western blotting in the relevant tissues. To confirm defective IFN-I signaling with STAT2 deletion, IFN-β stimulation of splenocytes from CMV-Cre Stat2 KO mice showed a lack of induction of canonical IFN-I target genes, confirming functional disruption of the pathway. In vivo, global Stat2 deletion significantly impaired the antitumor efficacy of IFN-β treatment. Similarly, lung fibroblasts isolated from globally deleted Stat2 KO mice showed defective antiviral responses to IFN-β. Tissue-specific Cre models demonstrated selective ablation of STAT2 in target compartments without affecting its expression in non-target tissues. Together, these studies expand our published conditional Stat2 KO findings and highlight the value of this model as a versatile platform for dissecting STAT2-dependent signaling pathways in a tissue- and disease-specific manner.