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 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.