A Human STAT3 Gain of Function Variant Drives Th17 Expansion and IL-22-dependent Skin Inflammation in a Model of Psoriasiform Dermatitis

Abstract

Patients with germline gain-of-function (GOF) variants in signal transducer and activator of transcription 3 (STAT3) present with early-onset polyautoimmunity, including psoriasis. STAT3 is a pleiotropic transcription factor that plays a role in the proliferation, survival, and function of many different cell types. In T cells, STAT3 is required for the polarization and function of Th17 cells and can inhibit development of peripheral Tregs. We hypothesized that STAT3 GOF variants enhance Th17 responses following an inflammatory stimulus, leading to autoimmune disease. To examine this, we generated a mouse model of STAT3 GOF using an amino acid substitution identified in patients (p.G421R). Aged STAT3 GOF mice develop spontaneous skin inflammation of the ears associated with increased neutrophil and T cell infiltration into the skin. The frequency of Th17 in the aged skin was also increased compared to age-matched WT littermates. In adult STAT3 GOF mice, Th17 polarization of naïve T cells was enhanced in vitro, indicating a potential for CD4 skewing toward Th17. To test if this would drive disease susceptibility in vivo, WT and STAT3 GOF mice were treated with topical imiquimod (IMQ). Following treatment, STAT3 GOF mice demonstrated increased ear swelling and an increased Th17 response in the skin and periphery. Adaptive lymphocytes mediated this response; however, CD8T cells and γδ T cells are not required. Analysis of T cell clonality by scRNA-seq revealed an increased frequency of expanded clones in untreated and IMQ-treated CD4 and CD8T cells of effector and exhausted subsets. Among the expanded clones, Il22 transcript was upregulated in STAT3 GOF IMQ-treated CD4s. IL-22 was then found to partially mediate the response to IMQ in STAT3 GOF. Using bone marrow chimeras, we identified a role for both radiosensitive and resistant cells in this inflammatory response. We also observed a competitive advantage for STAT3 GOF Th17 cells in the skin. Collectively, these data demonstrate that STAT3 GOF results in a cell-intrinsic skewing of T cells with a Th17 phenotype, suggesting a potential mechanism for the development of autoimmunity and a target for therapeutics in patients with STAT3 GOF syndrome.