Cross-species gene expression analysis identifies a type I interferon-associated transcriptional signature in Tregs from atopic dermatitis

Although regulatory T cells (Tregs) maintain immune tolerance, disease-relevant Treg molecular states in atopic dermatitis (AD) remain unclear. This study used an inducible mouse model of spontaneous AD-like dermatitis caused by combined Foxp3 and Bcl6 gene deletion and established a bacterial artificial chromosome reporter system to track Tregs after Foxp3 loss. Bulk RNA sequencing (RNA-seq) of splenic Tregs revealed robust induction of antiviral and type I interferon (IFN)-responsive gene programs in Foxp3 / Bcl6 -deficient Tregs. To assess its clinical relevance, single-cell RNA-seq data from patients with AD were reanalyzed. The analysis revealed that the ortholog-mapped mouse signature was selectively enriched in human Tregs, and type I IFN response signatures were elevated. Regulon analysis further implicated IFN-associated transcription factors, including IFN regulatory factor and signal transducer and activator of transcription family members, as candidate regulators of this program. These cross-species results highlight a type I IFN-associated Treg transcriptional state in AD and support the utility of this model for mechanistic studies of Treg-dependent disease processes.