Ex-Tregs: From controversial artifact to therapeutic target

Regulatory T cell (Treg) instability has evolved from a debated artifact into a central concept in immunology, though the mechanisms driving the transition from stable suppressor to 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. Core MessageTCR signal strength and inflammatory context determines whether a Treg stays stable (suppressive) or converts into an ex-Treg (pathogenic/effector). • The “Self vs Non-self” hypothesis explains regulatory T cell (Treg) instability. • Three pillars drive exTreg conversion: signals, epigenetics, and metabolism. • Ex-Tregs serve as an evolved checkpoint that balances tolerance and defense. • Targeting Treg stability offers therapeutic avenues for autoimmunity and cancer.