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

Reprogramming autoreactive CD4 effector T (T) cells into immunosuppressive regulatory T (T) cells represents a promising strategy for treating established autoimmune diseases. However, the stability and function of such reprogrammed T under inflammatory conditions remain unclear. Here, we show that demethylation of core T identity genes in T cells yields lineage-stable Effector T cell Reprogrammed T (ER-T). A single adoptive transfer of ER-T 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 cells, induced T from naïve precursors, and endogenous T, ER-T 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 cells as an effective approach to generate potent, stable T for the treatment of refractory autoimmune conditions.