@article{Li2026, 
author = {Liping Li and Minghui Li and Xuyu Zhou},
title = {Ex-Tregs: From controversial artifact to therapeutic target},
year = {2026},
journal = {hLife},
volume = {4},
number = {8},
pages = {467-485},
keywords = {regulatory T cells (Tregs), Treg instability, ex-regulatory T cells (ex-Tregs), FOXP3, epigenetic regulation, immune tolerance},
url = {https://www.sciopen.com/article/10.1016/j.hlife.2026.05.002},
doi = {10.1016/j.hlife.2026.05.002},
abstract = {Regulatory T cell (Treg) instability has evolved from a debated artifact into a central concept in immunology, though the mechanisms driving the transition from a stable suppressor to a pathogenic ex-regulatory T cell (ex-Treg) remain unclear. This review synthesizes findings from fate-mapping, epigenetic, and metabolic studies in mouse models and human systems, tracing the ex-Treg concept through three phases: controversy, epigenetic reconciliation, and current views. The Treg-specific demethylated region (TSDR) distinguishes truly committed Tregs from transient forkhead box P3 (FOXP3) expressers. Three interdependent factors—environmental stress (interleukin-1β [IL-1β], interleukin-6 [IL-6]), epigenetic erasure (ten-eleven translocation 2 [TET2] dysfunction leading to TSDR hypermethylation), and metabolic rewiring (mechanistic target of rapamycin [mTOR]-driven glycolysis)—cooperatively drive ex-Treg conversion. The “self vs non-self” hypothesis frames instability as an evolved checkpoint balancing tolerance with host defense. Ex-Tregs contribute to autoimmunity and aging but also offer therapeutic opportunities in cancer. Key uncertainties persist regarding ex-Treg heterogeneity, epigenetic reversibility, and translation to humans. Future directions should focus on biomarker discovery and engineering epigenetically stable Tregs for therapy. Collectively, these advances position Treg instability as a pivotal regulator of immune homeostasis and highlight the promise of therapeutically targeting this pathway to advance treatments for autoimmunity, aging, and cancer.}
}