STAT3 gain-of-function variants and T cell-mediated inflammation

Abstract 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. STAT3 polymorphisms have been linked to several common autoimmune disorders where the balance between Th17 and Tregs has been disrupted. Patients with germline gain-of-function variants in STAT3 present with a syndrome of early-onset poly-autoimmunity. We generated two mouse models of STAT3 GOF by CRISPR/Cas9. In these models, mice have a single point mutation, p.G421R or p.T716M, which are two of the exact amino acid substitutions identified in patients. Heterozygous STAT3 GOF mice do not show spontaneous disease or constitutive activation of STAT3 and instead display delayed STAT3 de-phosphorylation following IL-6 stimulation. We hypothesized that STAT3 GOF would enhance Th17 responses and found increased Th17 polarization from naïve STAT3 GOF T cells in vitro. To test whether this increased disease susceptibility in vivo, we treated WT and STAT3 GOF mice with topical imiquimod. Compared to WT, STAT3 GOF mice have more severe disease as demonstrated by ear swelling and epidermal thickness, as well as increased numbers of Th17 cells in peripheral organs at day 7 and in the skin at day 14. No difference was observed in IL-17+ γδ T cell populations in these organs at either time point. STAT3 GOF mice crossed to Rag 1 −/− or IL-22−/− show decreased disease severity, indicating that this response may be mediated by adaptive lymphocytes and IL-22 signaling. These data indicate that STAT3 GOF can exacerbate disease by enhancing Th17 responses that may drive autoimmunity.