Regulatory T (TReg) cells are crucial for the prevention of fatal autoimmunity in mice and humans. Forkhead box P3 (FOXP3)+ TReg cells are produced in the thymus and are also generated from conventional CD4+ T cells in peripheral sites. It has been suggested that FOXP3+ TReg cells might become unstable under certain inflammatory conditions and might adopt a phenotype that is more characteristic of effector CD4+ T cells. These suggestions have caused considerable debate in the field and have important implications for the therapeutic use of TReg cells. In this article, Nature Reviews Immunology asks several experts for their views on the plasticity and stability of TReg cells.
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S.S. acknowledges the daily discussions he had with his colleagues that helped him to write his comments for this article.
D.A.A.V. apologises to those investigators who contributed important observations related to the questions he covered that he could not discuss or quote owing to space limitations. D.A.A.V. is supported by the US National Institutes of Health (NIH) (grants AI091977, AI039480, AI052199, DK089125), American Asthma Foundation (grant10-0128), National Cancer Institute Comprehensive Cancer Center grant (CA21765) and ALSAC.
A.Y.R. is supported by an NIH grant (R37 AI034206) and is an investigator at the Howard Hughes Medical Center. R.E.N. is supported by an NIH Medical Scientist Training Program grant (GM07739) and a National Institute of Neurological Disorders and Stroke grant (1F31NS073203-01).
H.W. wishes to acknowledge the help of his colleagues D. Howie, R. Hilbrands and S. Cobbold in writing his comments for this article.
D.A.A.V. declares competing financial interests. He has submitted patents that are pending or granted, and is entitled to a share in net income generated from licensing of these patent rights for commercial development. He also consults for several biopharmaceutical companies.
S.S., R.E.N., A.R. and H.W. declare no competing financial interests.
- Asymmetric T cell division
A process by which two daughter cells can inherit different amounts of immune receptors and signalling components from a parent cell during T cell division. It has been suggested that this process occurs because of the polarity of the dividing cell that is associated with immunological synapse formation and that it could specify different fates to the progeny of an individual T cell.
- Conserved non-coding sequence 2
(CNS2). The element engaged in the positive auto-feedback loop that confers heritable maintenance of forkhead box P3 (FOXP3) expression once demethylated. Also known as the TSDR (TReg cell-specific demethylated region).
- CpG island
A sequence of 0.5–2 kilobases that is rich in CpG dinucleotides. CpG islands are mostly located upstream of housekeeping genes and also upstream of some tissue-specific genes. They are constitutively non-methylated in all animal cell types.
- Infectious tolerance
The ability of a tolerized population of T cells to induce tolerance in a new, naive population of T cells. Tolerance might be to the same antigens or to new antigens that are encountered in the same context (linked suppression). Newly tolerized T cells can, in turn, induce tolerance in other T cells.
- NOD mice
Non-obese diabetic (NOD) mice spontaneously develop a form of autoimmunity that closely resembles human type 1 diabetes.
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Sakaguchi, S., Vignali, D., Rudensky, A. et al. The plasticity and stability of regulatory T cells. Nat Rev Immunol 13, 461–467 (2013). https://doi.org/10.1038/nri3464
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