Interferons (IFNs) are soluble mediators of antiviral defense, with well-defined molecular mechanisms underlying their production and downstream response, as reviewed by others 1, 2, 3. In brief, IFNs are produced and secreted in response to infection through activation of pattern recognition receptors (PRRs). When the secreted IFNs bind their cognate receptors, transcription factors (e.g., signal transducer and activator of transcription (STAT) and interferon-regulatory factor (IRF) family) are activated to promote expression of interferon-stimulated genes (ISGs), which collectively contribute to an antiviral response. There are three types of IFN, classified by usage of different membrane-bound receptors. Type-I and -III IFNs have similar mechanisms of induction and ISG response, but type-I IFNs can stimulate almost every nucleated cell in the body, whereas responses to type-III IFNs are restricted to relatively few cell types, including epithelial cells 4, 5, 6, 7, 8, 9.

Studies of virus infection in the gastrointestinal (GI) tract defined an essential role for type-III IFNs in antiviral protection of the intestinal epithelium, whereas type-I IFNs play a larger role in nonepithelial cell types 10, 11. The basis for type-III IFN’s dominant role in the intestinal epithelium remains an active area of study, with implications for GI immunity and homeostasis. Additionally, the interaction between type-III IFN, type-I IFN, and other co-occurring cytokine responses within the intestine is a critical area of active investigation. The focus of this review will be on type-I and -III IFN in the GI tract, highlighting recent advances in our understanding of regulatory mechanisms, antiviral responses, roles in nonviral infections, and roles in homeostasis.