Constitutive Interferon Epsilon Expression Shapes Antiviral Epithelial States in the Female Reproductive Tract and...

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 Ifnε ^-/- mice and single-cell RNA sequencing to delineate IFNε function across distinct mucosal surfaces. In the FRT, Ifnε expression was restricted to specific epithelial subsets, was independent of estrous stage, and maintained basal ISG expression. IFNε was also retained intracellularly in primary human FRT-derived cells. Extending these analyses to the intestine, we found that IFNε is highly expressed in villous-tip enterocytes of the small intestine in vivo , where it sustains inflammatory enterocyte subsets and maintains type III IFN expression. Loss of Ifnε depleted these subsets and rendered mice more susceptible to enteric viral infection. Together, these findings establish IFNε as a constitutively expressed, spatially restricted IFN that coordinates mucosal antiviral defenses across both reproductive and gastrointestinal epithelial tissues.