Targeting the FOXP3-T-bet interaction to restore Treg stability in IFN-γ-driven autoimmunity.

Regulatory T-cell (Treg) stability is maintained by dynamic remodeling of the FOXP3 transcriptional complex, and disruption of this complex leads to Treg dysfunction and immune dysregulation. However, how specific FOXP3 mutations alter the dynamic remodeling of the FOXP3 complex and thereby contribute to pathogenic Treg reprogramming in IPEX syndrome remains unclear. Here, we demonstrate that predominant Th1 inflammation manifests in both FOXP3V408M IPEX patients and FOXP3V408M knock-in mice and reveal that the mutation intrinsically impairs Treg-mediated control of Th1 inflammation, revealing a distinct pathogenesis of this mutation in IPEX syndrome. Mechanistically, the V408M mutation disrupts the FOXP3-T-bet interaction, impairing the FOXP3-mediated restraint of T-bet-driven IFN-γ production and thereby contributing to increased Th1 inflammation. Using an AI-driven virtual screening approach, we identified a first-in-class small molecule, FM029, that directly binds to FOXP3 and reinforces its interaction with T-bet. FM029 strongly suppressed Treg-derived IFN-γ production and alleviated IFN-γ-driven tissue inflammation in both FOXP3V408M mice and an acute colitis model. Collectively, these findings establish the FOXP3-T-bet interaction as a central checkpoint that governs Treg stability and IFN-γ-driven Th1 pathology, providing a proof-of-concept that pharmacologic stabilization of the FOXP3-T-bet interaction can mitigate IFN-γ-driven immune disorders.