Tu145 - STAT3 Gain-of-function Variants and T Cell-mediated Inflammation

STAT3 is a 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. Patients with germline gain-of-function variants in STAT3 present with early-onset poly-autoimmunity, including psoriasis. 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). Heterozygous STAT3 GOF mice display delayed STAT3 de-phosphorylation and increased Th17 polarization of naïve T cells in vitro. To test if this would drive disease susceptibility in vivo, WT and STAT3 GOF mice were treated with topical imiquimod. Following treatment, STAT3 GOF mice demonstrated increased ear swelling and an increased Th17 response in the skin and periphery. Adaptive lymphocytes and IL-22 mediated this response; however, γδ T cells are not required. 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 in patients with STAT3 GOF syndrome.