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FOXP3+ regulatory T cells in the human immune system

Nature Reviews Immunology volume 10, pages 490–500 (2010)Cite this article

Subjects

Key Points

  • Regulatory T (TReg) cells are potent mediators of dominant tolerance in the periphery. The study of TReg cells in many models of animal disease has revealed their ability to prevent autoimmune pathogenesis and to restore immune homeostasis but also to promote cancer growth by repressing antitumour immune responses. Such findings have made TReg cells a promising target for clinical application.

  • Confusion as to the mechanism of the identity, function and stability of human TReg cells has, to date, impeded the general therapeutic use of these cells.

  • Several recent studies have suggested that human TReg cells possess functional and phenotypic diversity that has not been previously apparent. Indeed, based on recent findings, forkhead box P3 (FOXP3)+CD4+ T cells can be divided into several functionally unique populations based on their expression of CD45RA, CD45RO, HLA-DR and FOXP3.

  • A more detailed characterization of the ontogeny, phenotype and suppressive function of human TReg cells is needed for the study of TReg cells in the pathophysiology of autoimmune diseases, allergy, transplantation, pregnancy, infection and cancer.

  • Although several issues regarding long term reliability and safety still need to be addressed, TReg cell-based therapy is a promising therapeutic perspective that should be applicable in a wide range of immune diseases.

Abstract

Forkhead box P3 (FOXP3)+ regulatory T (TReg) cells are potent mediators of dominant self tolerance in the periphery. But confusion as to the identity, stability and suppressive function of human TReg cells has, to date, impeded the general therapeutic use of these cells. Recent studies have suggested that human TReg cells are functionally and phenotypically diverse. Here we discuss recent findings regarding human TReg cells, including the ontogeny and development of TReg cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by TReg cell subsets and factors that regulate TReg cell lineage commitment. We discuss future studies that are needed for the successful therapeutic use of human TReg cells.

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Figure 1: FOXP3 expression in human TReg cells.
Figure 2: TReg cell differentiation.

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Acknowledgements

M.M. is currently supported by Fondation pour la Recherche Medicale and by the Japan Society for the Promotion of Science. This work was supported by grants-in-aid from the Ministry of Education, Sports and Culture of Japan, by US NIH grants: UO1DK6192601, RO1NS2424710, PO1AI39671 and PO1NS38037 and grants from the National Multiple Sclerosis Society: RG2172C9 and RG3308A10. M.M.

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Author notes

  1. All authors contributed equally to this article.

  2. Internal Medicine Department 2, Laboratoire d'immunochimie and Laboratoire d'immunologie cellulaire et tissulaire (INSERM UMR-S945), AP-HP, Hôpital Pitié-Salpêtrière, 75013 Paris, France.

  3. Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, USA.

  4. Harvard Medical School, Boston, Massachusetts 02115, USA, and Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520, USA.

Authors and Affiliations

  1. Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, 606-8507, Kyoto, Japan

    Shimon Sakaguchi, Makoto Miyara, Cristina M. Costantino & David A. Hafler

  2. WPI Immunology Frontier Research Center, Osaka University, 565-0871, Suita, Japan

    Shimon Sakaguchi, Makoto Miyara, Cristina M. Costantino & David A. Hafler

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  1. Shimon Sakaguchi
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Glossary

Dominant self tolerance

Refers to the active suppression of an autoimmune response in vitro or in vivo by suppressor cells, including regulatory T cells. By contrast, deletional tolerance and anergy are referred to as recessive or passive self tolerance mechanisms. Dominant self tolerance is transferable to naive recipients, whereas recessive self tolerance is not.

Central tolerance

Self tolerance that is created at the level of the central lymphoid organs. Developing T cells in the thymus, and B cells in the bone marrow, that strongly recognize self antigen face deletion or anergy induction.

Self tolerance

Tolerance to an individual's own tissue antigens that is achieved through both central and peripheral tolerance mechanisms, including T cell deletion, anergy and immune regulation. Without both central and peripheral tolerance mechanisms the immune system would be unable to distinguish self from foreign antigen, resulting in autoimmunity.

Hassall's corpuscles

Small clusters or concentric whorls of stratified keratinizing epithelium in the thymic medulla. They are probably end-stage differentiated epithelial cells that participate in negative selection of thymocytes and/or that undergo apoptosis themselves.

Scurfy mice

Mice with a spontaneous mutation in Foxp3, which leads to a rapidly fatal lymphoproliferative disease, causing death by ∼4 weeks of age.

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome

A disease caused by mutations in FOXP3 and characterized by refractory enteritis, autoimmune endocrinopathies, including type 1 diabetes, thyroiditis and allergy.

Anergy

A state of non-responsiveness to antigen. Anergic B or T cells cannot respond to their cognate antigens under optimal conditions of stimulation.

Apoptosis

A common form of cell death, which is also known as intrinsic or programmed cell death. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation.

NOD/Shi-scid Il2rg/−/− (NOG) mice

Immunodeficient mice that can be adoptively transferred with human cells. When reconstituted with human cord blood stem cells, these mice allow the analysis of the behaviour of human cells in vivo.

Thymic involution

The age-dependent decrease of thymic epithelial volume, which results in decreased production of T cells.

Rapamycin

An immunosuppressive drug that does not prevent T cell activation but blocks IL-2-mediated clonal expansion by blocking mTOR (mammalian target of rapamycin).

Deacetylation

A post-translational modification of chromatin components, particularly histones. It correlates with actively transcribed chromatin. Histone deacetylases have been identified as components of nuclear co-repressor complexes, which reverse the actions of histone acetyltransferases, thereby inhibiting gene transcription.

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Sakaguchi, S., Miyara, M., Costantino, C. et al. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10, 490–500 (2010). https://doi.org/10.1038/nri2785

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