Regulatory T cells epigenetically reprogrammed from autoreactive effector T cells mitigate established autoimmunity

Reprogramming autoreactive CD4⁺ effector T (T_eff) cells into immunosuppressive regulatory T (T_reg) cells represents a promising strategy for treating established autoimmune diseases. However, the stability and function of such reprogrammed T_regs under inflammatory conditions remain unclear. Here, we show that demethylation of core T_reg identity genes in T_eff cells yields lineage-stable Effector T cell Reprogrammed T_regs (ER-T_regs). A single adoptive transfer of ER-T_regs not only prevents autoimmune neuroinflammation in mice when given before disease onset but also arrests its progression when administered after onset. Compared to Foxp3-overexpressing T_eff cells, induced T_regs from naïve precursors, and endogenous T_regs, ER-T_regs provide superior protection against autoimmune neuroinflammation. This enhanced efficacy stems from their inherited autoantigen specificity and selectively preserved effector-cell transcriptional programs, which together bolster their fitness in inflammatory environments and enhance their suppressive capacity. Our results establish epigenetic reprogramming of autoreactive T_eff cells as an effective approach to generate potent, stable T_regs for the treatment of refractory autoimmune conditions.