STAT1 Gain-of-function Leads to Dysfunctional T Regulatory Cells

Abstract Text: Understanding the pathogenesis of Type 1 diabetes (T1D) is critical in developing effective treatments. T1D results from immune dysfunction leading to the destruction of insulin-producing β-cells, influenced by genetic predispositions and environmental factors. However, the exact mechanisms remain elusive. This study explores the role of signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations in T1D, known for causing immune dysregulation, including T1D and thyroiditis. We developed a novel NOD.STAT1 GOF knock-in mouse model, incorporating the R247W mutation associated with human STAT1 hyperactivity and T1D. This model replicates key aspects of the human STAT1 GOF phenotype, with the mice exhibiting autoimmune diseases, including colitis and skin inflammation. Notably, T cells from these mice secreted elevated levels of IFN-γ, mirroring human pathology. Furthermore, crossing these mice with T cell-restricted BDC2.5 NOD mice resulted in accelerated diabetes onset. Our single-cell analysis revealed decreased CD25 transcript levels in T regulatory cells, confirmed by flow cytometry. These findings highlight a critical function of STAT1 in modulating T regulatory cells, suggesting potential therapeutic interventions using JAK inhibitors.