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

Tyler R. Colson; James J. Cameron; Hayley I. Muendlein; Mei-An Nolan; Jamie L. Leiriao; James H. Kim; Alexander N. Poltorak; Xudong Li

doi:10.1172/jci.insight.185581

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

Tyler R. Colson,¹ James J. Cameron,¹ Hayley I. Muendlein,² Mei-An Nolan,¹ Jamie L. Leiriao,¹ James H. Kim,² Alexander N. Poltorak,¹ and Xudong Li¹

Published July 31, 2025 - More info

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Abstract

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 epigenetic activation 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.

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

Tyler R. Colson,¹ James J. Cameron,¹ Hayley I. Muendlein,² Mei-An Nolan,¹ Jamie L. Leiriao,¹ James H. Kim,² Alexander N. Poltorak,¹ and Xudong Li¹

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

Tyler R. Colson,1 James J. Cameron,1 Hayley I. Muendlein,2 Mei-An Nolan,1 Jamie L. Leiriao,1 James H. Kim,2 Alexander N. Poltorak,1 and Xudong Li1

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Tyler R. Colson,¹ James J. Cameron,¹ Hayley I. Muendlein,² Mei-An Nolan,¹ Jamie L. Leiriao,¹ James H. Kim,² Alexander N. Poltorak,¹ and Xudong Li¹