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Peer-reviewedCC BY-NC-NDHLife

Ex-Tregs: From controversial artifact to therapeutic target.

  • Liping Li1,2
  • Minghui Li3,4,5
  • Xuyu Zhou1,2
5 affiliations
  1. 1CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  2. 2Medical School, University of Chinese Academy of Sciences, Beijing, China.
  3. 3Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
  4. 4HBV Infection, Clinical Cure and Immunology Joint Laboratory for Clinical Medicine, Capital Medical University, Beijing, China.
  5. 5Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China.
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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.

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Cite

BibTeXRIS
BibTeX
@article{li2026extregs,
  title = {{Ex-Tregs: From controversial artifact to therapeutic target.}},
  author = {Liping Li and Minghui Li and Xuyu Zhou},
  journal = {HLife},
  year = {2026},
  month = may,
  doi = {10.1016/j.hlife.2026.05.002},
  url = {https://europepmc.org/article/MED/42903823},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Ex-Tregs: From controversial artifact to therapeutic target.
AU  - Liping Li
AU  - Minghui Li
AU  - Xuyu Zhou
PY  - 2026
DA  - 2026/05/19
JO  - HLife
DO  - 10.1016/j.hlife.2026.05.002
UR  - https://europepmc.org/article/MED/42903823
AB  - 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.
SN  - 2949-9283
ER  -