Balancing IL-17-mediated protection and IFN-γ-driven pathology at mucocutaneous barriers

Mucocutaneous surfaces rely on IL-17-producing lymphocytes to preserve barrier integrity and prevent bacterial and fungal overgrowth. Accordingly, genetic or pharmacological IL-17 deficiencies lead to mucocutaneous infections. Interferon (IFN)-γ mediates host defense against intracellular pathogens, but excessive mucosal IFN-γ activity can paradoxically impair epithelial integrity and promote infection, as shown in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy-associated oral candidiasis, even with intact IL-17 responses. Further evidence for IFN-γ-driven pathology is emerging in bacterial, fungal, and protozoal infections at mucocutaneous tissues. Together, these findings support a model in which IL-17 promotes barrier resistance, whereas unchecked IFN-γ erodes it. Collectively, they advance the concept that although mucocutaneous infections are classically caused by immunodeficiency, epithelial disruption by immunopathology represents a novel and underappreciated mechanism of infection susceptibility at barrier sites.