FOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (T_reg) cells. CD4⁺ T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous T_reg-like cells, some very similar to normal T_reg cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4⁺ T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal T_reg cells exerted dominant suppression, quenching the disease signature and revealing in mutant T_reg-like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes T_reg cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering T_reg cell dysfunction. Accordingly, interleukin-2 treatment improved the T_reg-like compartment and survival.