IFN-κ directs antiviral immunity in human skin

Inducible expression of type I IFNs is a well-established host innate defense mechanism to limit virus infection. Yet, many viruses have evolved strategies to suppress the induction of these cytokines to enhance replication, spread, and transmission between hosts. Whether additional antiviral mechanisms protect against infection when inducible responses are compromised is not well understood. Here, we demonstrate that human keratinocytes preemptively protect the skin against virus infection through constitutive production of IFN-kappa (IFN-κ), a poorly studied type I IFN family member. We find that constitutive IFNK expression protects keratinocytes against skin tropic RNA and DNA viruses, including vesicular stomatitis virus (VSV) and herpes simplex virus-1 (HSV-1). Using a human skin organoid model, we further demonstrate that keratinocyte-derived IFN-κ establishes an antiviral state in dermal fibroblasts. Genetic and chemical analysis of the type I IFN receptor (IFNAR) signaling pathway in monocultured keratinocytes and skin organoids revealed that distinct pathways control VSV and HSV-1 replication. While canonical JAK-STAT signaling provided protection against VSV, HSV-1 infection was controlled through a JAK-STAT-independent mechanism. Using transcriptomic analysis, we further identified an IFN-κ-dependent gene signature in keratinocytes that is not similarly driven by other type I IFNs. Together, this work establishes constitutive IFN-κ production by keratinocytes as a broadly antiviral tissue autonomous defense mechanism.