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Regulatory lymphocytes

Regulatory T cells under scrutiny

Nature Reviews Immunology volume 3, pages 189–198 (2003)Cite this article

An Erratum to this article was published on 01 June 2003

Key Points

  • Selective T-cell depletion induces organ-specific autoimmune diseases.

  • The onset of such autoimmune diseases can be prevented by the administration of T-cell subsets defined by various overlapping, but not discriminating, membrane markers, such as CD25 (the α-chain of the interleukin-2 (IL-2) receptor), CD62L (L-selectin) and CD45RB. CD25 is probably the best marker, but it is not an absolute one.

  • Suppression can be mediated in vitro by CD25+ T cells in the absence of cytokines (necessity of cell–cell contact). Conversely, in vivo suppression seems to involve cytokines, the nature of which varies with the experimental model. Transforming growth factor-β and IL-10 seem to have central roles.

  • Regulatory T cells are diverse. In addition to CD25+ and T helper 2 (TH2) cells, other cell types can mediate regulation in certain settings, such as TR1 cells, CD8+ T cells, natural killer (NK) cells, NKT cells and γδ T cells.

  • Indirect arguments indicate that regulatory T cells are antigen specific, notably CD25+, TH2 and TR1 cells. The role of competition for homeostatic signals (such as self-peptide–MHC and IL-7) might also be important.

  • Regulatory T cells provide an explanation for several states of peripheral tolerance induced in transplantation and autoimmunity, as shown by the transfer of tolerance by CD4+ T cells.

  • Regulatory T-cell diversity poses the problems of the identity of the regulatory T cells that are involved in each model and, more generally, of their functional specialization.

Abstract

Having been long debated, the notion of suppressor T cells — renamed regulatory T cells — is back on the map, but many questions remain regarding the nature of these regulatory cells. Are they specialized cells? What are their phenotype, antigen specificity, mode of action and, above all, biological (and immunopathological) relevance? The predominant role of naturally occurring CD4+CD25+ T cells has been emphasized recently. Other cell types, however, contribute to immunoregulation also, whether they arise spontaneously during ontogeny or during the course of an adaptive immune response.

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Figure 1: Experimental evidence for active tolerance involving regulatory T cells.
Figure 2: Contrasting models of the antigen specificity and function of regulatory T cells.
Figure 3: The diversity of regulatory T cells.

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Acknowledgements

I wish to acknowledge constructive discussion with R. Zinkernagel, who was very helpful in my phrasing and balancing of this reflection on regulatory T cells. I also wish to thank H. Feillet for her outstanding help in documentation, and S. Clonan for excellent editorial assistance.

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  1. Hôpital Necker, INSERM U580, 161 rue de Sèvres, Paris, 75743 Cedex 15, France

    Jean François Bach

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DATABASES

LocusLink

CD2

CD4

CD8

CD25

CD40L

CD45

CD62L

CTLA4

GAD

IFN-γ

IL-2

IL-4

IL-7

IL-10

MBP

PLP

Rag1/2

RT6

TGF-β

OMIM

multiple sclerosis

type 1 diabetes

Glossary

IMMUNOREGULATION

The regulation of immune responses mediated by either antibody or T cells, independently from the underlying effector mechanism.

NON-OBESE DIABETIC MICE

(NOD mice). An inbred strain of mice that spontaneously develop T-cell-mediated autoimmune diabetes.

CYCLOSPORINE A

An immunosuppressive drug that inhibits calcineurin, a Ca2+-dependent serine/threonine phosphatase that is necessary for nuclear translocation of the transcription factor NFAT.

INFECTIOUS TOLERANCE

The extension of tolerance to naive T cells that have not been exposed to the tolerizing antigen.

EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

(EAE). An animal model of multiple sclerosis — a chronic demyelinating disease in humans. In animals, EAE is induced by the injection of several myelin-sheath antigens, including myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein, together with adjuvant.

CYCLOPHOSPHAMIDE

A DNA-alkylating agent that is used widely as an anti-tumour agent or an immunosuppressive agent. Cyclophosphamide has been shown to destroy certain subsets of lymphocytes preferentially, including B cells and regulatory cells.

ALTERED PEPTIDE LIGAND

(APL). A synthetic peptide homologous to a natural peptide that has a differential capacity to induce effector versus regulatory T cells. APLs can stimulate regulatory cells without inducing effector cells.

BYSTANDER SUPPRESSION

The extension of tolerogen-induced suppression of an immune response to immune responses that are directed against antigens not structurally related to the tolerogen but expressed by the same target cell.

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François Bach, J. Regulatory T cells under scrutiny. Nat Rev Immunol 3, 189–198 (2003). https://doi.org/10.1038/nri1026

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