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.