A human STAT3 gain of function variant drives Th17 expansion and IL-22 dependent skin inflammation in a model of psoriasiform dermatitis

Germline gain-of-function (GOF) variants in STAT3 cause early-onset poly-autoimmunity and immune dysregulation. STAT3 is a pleiotropic transcription factor that affects the induction and regulation of immune responses, with diverse effects on the immune response. Using a mouse model of STAT3 GOF (p.G421R), we observed spontaneous and imiquimod (IMQ)-induced skin inflammation with increased cell-intrinsic local Th17 responses. CD4+ T cells were required and sufficient to drive skin inflammation, and upregulated Il22 expression in expanded clones. However, certain aspects of disease, including epidermal thickness, required the presence of STAT3 GOF in epithelial cells. Treatment with a JAK inhibitor improved skin disease, without affecting local Th17 recruitment and cytokine production. Collectively, these data support a role for a Th17 response and in the development of organ-specific immune dysregulation in STAT3 GOF, and also suggest that the presence of STAT3 GOF in tissues is important for disease and can be targeted with JAK inhibition.