Introduction: Defective mucosal and skin host defense mechanisms are the hallmarks of the primary immunodeficiency chronic mucocutaneous candidiasis (CMC). We previously reported that heterozygous mutations in the signal transducer and activator of transcription 1 (STAT1) gene are responsible for autosomal dominant CMC. Moreover, we demonstrated that gain-of-function (GOF) mutations of STAT1 lead to its hyperphosphorylation and subsequent impairment of Th17 responses, finally resulting in a severe mucocutaneous Candida albicans infection. Although CMC manifests itself at the level of epithelia (skin and oral mucosa), research has so far been limited to the study of immune cells. Using genetically defined epidermal cells, either wild type or carrying STAT1 GOF mutations, we investigated their response to proinflammatory cytokines, with respect to skin barrier and host defense gene expression 
Methods and Materials: We generated 3D epidermal equivalents from keratinocytes of healthy controls and CMC patients (STAT1 GOF), and stimulated these with IL-17, IL-22 or IFNγ. The cellular responses were evaluated by immunohistochemistry. 
Results: Stimulation by IFNγ, but not by Th17 cytokines, caused abnormal epidermal morphology and a strongly reduced expression of Late Cornified Envelope 3 (LCE3) proteins. We found that, in addition to their known antibacterial activity, LCE3 proteins had antifungal activity against Candida albicans. 
Discussion: This study demonstrates that epithelia of patients with a STAT1 GOF mutation have a functional defect that becomes apparent when immune cell-derived IFNγ is present. This results in structural abnormality of the epidermis and compromises the innate anti-Candida activity of the tissue.

STAT1 gain-of-function compromises skin host defense in the context of IFN-γ signaling