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Targeting the FOXP3–T-bet interaction to restore Treg stability in IFN-γ–driven autoimmunity [CUT&Tag/ATAC-seq]

ABSTRACT: IPEX syndrome is a rare spontaneous autoimmune disease caused by the deficiency or mutations of FOXP3, the dominant transcription factor of regulatory T cells (Tregs). Here, by exploring the pathogenic mechanism of IPEX syndrome, we identified for the first time that FOXP3 physically interacted with T-bet to repress IFNγ production in Tregs. This interaction, independent of T-bet abundance, was essential for restraining IFNγ-mediated Th1 immune response and preventing Treg perturbation. Notably, FOXP3 p.V408M mutation disrupted FOXP3-T-bet interaction, unleashing T-bet-driven IFNγ excessive production and Treg perturbation characterized by impaired suppressive activity on extrinsic Th1 immune response.

ORGANISM(S): Mus musculus

PROVIDER: GSE252269 | GEO | 2025/12/31

REPOSITORIES: GEO

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

Project description:Regulatory T cell (Treg) stability is maintained by dynamic remodeling of the FOXP3 transcriptional complex, and its disruption 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, by uncovering the distinctive pathogenesis of FOXP3V408M mutation in IPEX syndrome, we demonstrate that the FOXP3–T-bet interaction fine-tunes Treg function by repressing IFN-γ production, thereby preventing Th1-driven inflammation. Using an AI-driven virtual screening approach, we identified a first-in-class small molecule, 430C10, that directly binds FOXP3 and reinforces its interaction with T-bet. 430C10 robustly suppressed Treg-derived IFN-γ production and alleviated IFN-γ-driven tissue inflammation in FOXP3V408M knock-in mice as well as in models of acute colitis. Collectively, these findings establish the FOXP3–T-bet interaction as a central checkpoint governing Treg stability and IFN-γ-driven Th1 pathology, providing proof-of-concept that pharmacologic stabilization of FOXP3–T-bet interaction can mitigate IFN-γ–driven immune disorders.

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