IFN Epsilon in the Female Reproductive Tract: From Host Defense to Epithelial Homeostasis and Diseases

Interferon epsilon (IFNε), a unique type I IFN, is highly abundant in the female reproductive tract (FRT). Unlike IFNα and IFNβ, which are expressed at low or undetectable levels at the baseline and are strongly induced following pattern-recognition receptor activation, IFNε is constitutively expressed in the epithelium at mucosal tissues. Its expression is regulated by hormones and inflammatory cytokines. Its responsiveness to viral infection and Toll-like receptor activation varies across cell types. This distinctive regulatory profile positions IFNε as a preemptive component of mucosal defense. Studies in mice and human FRT tissues have established important roles for IFNε in maintaining expression of genes involved in epithelial and tissue structure as well as basal interferon-stimulated genes restricting sexually transmitted pathogens, including herpes simplex virus-2, Chlamydia, human immunodeficiency virus, and Zika virus. IFNε also shapes local immune responses, including uterine natural killer-cell recruitment and activation. However, its effects are not uniformly protective: Neisseria gonorrhoeae can exploit IFNε-dependent changes in sialic-acid metabolism to promote persistence. Recent work further broadens the IFNε paradigm beyond antimicrobial defense. IFNε-deficient mice exhibit cervicovaginal epithelial abnormalities and altered antiviral epithelial states, while IFNε has emerged as an intrinsic tumor suppressor in the fallopian tube/ovarian cancer axis. Human studies also implicate IFNε in pregnancy, cervical HPV responses, and cervical cancer, although the direction and mechanisms of these associations remain unknown. Here, we review the expression, regulation, signaling, and biological functions of IFNε in the FRT, reconcile emerging evidence for tissue- and context-specific actions, and discuss key unanswered questions concerning epithelial homeostasis, receptor usage, reproductive physiology, infection, and gynecologic malignancy.