Constitutive interferon epsilon expression shapes antiviral epithelial states in the female reproductive tract and intestine.

Antiviral defenses at mucosal barriers are essential for preventing viral entry and systemic infection. Interferon epsilon (IFNε) is a unique type I IFN that, unlike other family members, is not induced by infection but is constitutively expressed in epithelial tissues. IFNε was initially characterized in the female reproductive tract (FRT), where it provides broad antiviral protection, but its roles outside the FRT remain poorly defined. Here, we used IMPORTANCE: Interferon epsilon (IFNε) is a unique type I IFN that, unlike other family members, is not induced by infection but is constitutively expressed in epithelial tissues. In this manuscript, we define the epithelial cell types that constitutively express IFNε in the uterus and small intestine at a single-cell resolution. We show that mice lacking IFNε lose key antiviral defenses in a tissue-dependent manner; uterine epithelial cells have diminished basal ISG expression, and key populations of cytokine-expressing enterocytes are absent from the small intestine. In the intestine, this correlates with increased susceptibility to infection with an enteric virus in mice. These findings establish IFNε as a key contributor to mucosal immunity, sustaining antiviral defenses within tissue-specific epithelial cells of both the female reproductive tract and intestine, and broaden our understanding of its role beyond traditional pathogen-induced interferon responses.