Suppression by human FOXP3⁺ regulatory T cells requires FOXP3-TIP60 interactions

CD4⁺FOXP3⁺ regulatory T (T_reg) cells are critical mediators of immune tolerance, and their deficiency owing to FOXP3 mutations in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) patients results in severe autoimmunity. Different FOXP3 mutations result in a wide range of disease severity, reflecting the relative importance of the affected residues in the integrity of the FOXP3 protein and its various molecular interactions. We characterized the cellular and molecular impact of the most common IPEX mutation, p.A384T, on patient-derived T_reg cells. We found that the p.A384T mutation abrogated the suppressive capacity of T_reg cells while preserving FOXP3's ability to repress inflammatory cytokine production. This selective functional impairment is partly due to a specific disruption of FOXP3^A384T binding to the histone acetyltransferase Tat-interacting protein 60 (TIP60) (KAT5) and can be corrected using allosteric modifiers that enhance FOXP3-TIP60 interaction. These findings reveal the functional impact of TIP60 in FOXP3-driven T_reg biology and provide a potential target for therapeutic manipulation of T_reg activity.