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

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 IFN? production in Tregs. This interaction, independent of T-bet abundance, was essential for restraining IFN?-mediated Th1 immune response and preventing Treg perturbation. Notably, FOXP3 p.V408M mutation disrupted FOXP3-T-bet interaction, unleashing T-bet-driven IFN? excessive production and Treg perturbation characterized by impaired suppressive activity on extrinsic Th1 immune response. Overall design: We used splenic CD4+CD25+ Treg cells sorted from Foxp3WT and Foxp3V408M mice for Foxp3 and T-bet CUT&Tag and ATAC-seq.