Natural regulatory T cells: mechanisms of suppression

doi:10.1016/j.molmed.2007.01.003

Trends in Molecular Medicine

Volume 13, Issue 3, March 2007, Pages 108-116

https://doi.org/10.1016/j.molmed.2007.01.003 Get rights and content

Natural FOXP3⁺CD25⁺CD4⁺ regulatory T cells (Tregs) actively suppress pathological and physiological immune responses, contributing to the maintenance of immunological self-tolerance and immune homeostasis. Various molecular and cellular events have been described to explain the mechanism(s) of Treg-mediated suppression. However, none of the proposed mechanisms can explain all aspects of suppression. It is probable that various combinations of several mechanisms are operating, depending on the milieu and the type of immune responses, although there might be a single key mechanism that has a predominant role. Further studies of suppression and search for Treg-specific cell surface molecules are required for potential clinical application to treat and prevent immunological diseases and to control immune responses for the benefit of the host.

Section snippets

Introduction: natural regulatory T cells

The immune system protects the host from a myriad of pathogenic microbes while controlling aberrant or excessive immune responses that are harmful to the host. How this is achieved is a key issue in immunology. In addition to intrinsic control of lymphocytes, for example, via apoptosis of immature self-reactive lymphocytes upon exposure to self-antigen or activation-induced cell death of mature effector cells, there is evidence that a subpopulation of T cells, called regulatory T cells (Tregs),

FOXP3: the key controller of development and function of natural Tregs

FOXP3 is specifically expressed in CD25⁺CD4⁺ natural Tregs in rodents, and controls their development and function 13, 14, 15. In the thymus, FOXP3 expression starts at the late double-positive stage, and FOXP3⁺CD4⁺ Tregs can be detected in mice from day 3 after birth, showing a good correlation with the finding that thymectomy on day 3 after birth produces organ-specific autoimmune disease, which can be prevented by inoculation of CD25⁺CD4⁺ natural Tregs 1, 16. Mutations of the FOXP3 gene lead

Mechanisms of suppression

There is accumulating evidence that FOXP3⁺CD25⁺CD4⁺ natural Tregs suppress the activation and/or expansion of multiple types of immunocompetent cells. It was first shown that they suppress the activation and expansion of CD4⁺ T cells, as illustrated by the experiment in which Treg depletion induces CD4⁺ T cell-mediated autoimmune disease, and inoculation of Tregs inhibits the development of disease [2]. Inoculation of natural Tregs also inhibits CD4⁺ T cell-mediated autoimmune disease in

Control of Treg-mediated suppression

Whatever the mechanisms of suppression are, it is necessary to control the magnitude of Treg-mediated suppression for the benefit of the host because too much suppression might lead to immunosuppression and render the host susceptible to infection and cancer, and too low suppression might elicit autoimmunity and allergy. During microbial infection in particular, Treg suppression needs to be attenuated for provoking effective microbe-specific suppression while too potent anti-microbial immune

Therapeutic perspectives in humans

Human Tregs were initially defined as the 1–2% of CD4⁺ T cells that express the highest levels of CD25 because this CD25^highCD4⁺ population was shown to be highly suppressive in suppression assay in vitro [75]. FOXP3⁺CD4⁺ T cells represent ∼6% of human CD4⁺ cells. However, it is still not clear whether FOXP3 is a specific marker for Tregs in humans because activated T cells can transiently express FOXP3 albeit at lower levels than natural CD25^highCD4⁺ Tregs [76]. Recent studies have shown that

Concluding remarks

As discussed in this review, it is still controversial how Tregs suppress other T cells at the molecular level. It is likely that more than one mechanism of suppression operate in Treg-mediated control of immune responses and that suppression is the result of a combination of some of these mechanisms. It is also probable that various factors contribute to determining the magnitude of suppression; such factors involve the strength and the nature of the immune stimulus. Further studies of the

Acknowledgements

We apologize to those researchers whose work has not been cited in this review owing to space restrictions. We thank Kajsa Wing for critical reading of the manuscript. M. Miyara was supported by the Fondation pour la Recherche Médicale and S. Sakaguchi by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Human Welfare of Japan.

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Trends in Molecular Medicine

ReviewNatural regulatory T cells: mechanisms of suppression

Section snippets

Introduction: natural regulatory T cells

FOXP3: the key controller of development and function of natural Tregs

Mechanisms of suppression

Control of Treg-mediated suppression

Therapeutic perspectives in humans

Concluding remarks

Acknowledgements

Semin. Cancer Biol.

J Allergy Clin Immunol

Cell

Lab. Invest.

Blood

Immunity

Blood

Immunity

Blood

Blood

Immunity

Blood

Blood

Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses

Annu. Rev. Immunol.

Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases

J. Immunol.

FOXP3 acts as a rheostat of the immune response

Immunol. Rev.

Regulatory T cells: friend or foe in immunity to infection?

Nat. Rev. Immunol.

Induction of transplantation tolerance via regulatory T cells

Inflamm. Allergy Drug Targets

Regulatory T cells in pregnancy

Springer Semin. Immunopathol.

Regulation of immune responses by T cells

N. Engl. J. Med.

Interleukin-10-secreting type 1 regulatory T cells in rodents and humans

Immunol. Rev.

In vivo instruction of suppressor commitment in naive T cells

J. Exp. Med.

Inducing and expanding regulatory T cell populations by foreign antigen

Nat. Immunol.

Foxp3 programs the development and function of CD4+CD25+ regulatory T cells

Nat. Immunol.

Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self

Nat. Immunol.

FOXP3: of mice and men

Annu. Rev. Immunol.

Developmental regulation of Foxp3 expression during ontogeny

J. Exp. Med.

Control of regulatory T cell development by the transcription factor Foxp3

Science

Molecular mechanisms underlying FOXP3 induction in human T cells

J. Immunol.

Foxp3 interacts with nuclear factor of activated T cells and NF-κB to repress cytokine gene expression and effector functions of T helper cells

Proc. Natl. Acad. Sci. U. S. A.

Foxp3 represses retroviral transcription by targeting both NF-κB and CREB pathways

PLoS Pathog

Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis

Int. Immunol.

Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells

J. Immunol.

Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state

Int. Immunol.

CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production

J. Exp. Med.

Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells

J. Immunol.

TGF-β 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice

J. Immunol.

CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-β-dependent manner

J. Exp. Med.

Human CD4+ CD25+ regulatory T cells suppress NKT cell functions

Cancer Res.

Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells

J. Immunol.

Human cd25+cd4+ t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function

J. Exp. Med.

CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses

Review
Natural regulatory T cells: mechanisms of suppression

Naturally arising CD4⁺ regulatory T cells for immunologic self-tolerance and negative control of immune responses

Foxp3 programs the development and function of CD4⁺CD25⁺ regulatory T cells

Naturally arising Foxp3-expressing CD25⁺CD4⁺ regulatory T cells in immunological tolerance to self and non-self

Foxp3-dependent and -independent molecules specific for CD25⁺CD4⁺ natural regulatory T cells revealed by DNA microarray analysis

Cutting edge: control of CD8⁺ T cell activation by CD4⁺CD25⁺ immunoregulatory cells

Immunologic self-tolerance maintained by CD25⁺CD4⁺ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state

CD4⁺CD25⁺ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production

Cutting edge: direct suppression of B cells by CD4⁺ CD25⁺ regulatory T cells

TGF-β 1 plays an important role in the mechanism of CD4⁺CD25⁺ regulatory T cell activity in both humans and mice

CD4⁺CD25⁺ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-β-dependent manner

Human CD4⁺ CD25⁺ regulatory T cells suppress NKT cell functions

Cutting edge: human CD4⁺CD25⁺ T cells restrain the maturation and antigen-presenting function of dendritic cells

Human cd25⁺cd4⁺ t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function

CD4⁺CD25⁺ T cells regulate virus-specific primary and memory CD8⁺ T cell responses

Suppressor effector function of CD4⁺CD25⁺ immunoregulatory T cells is antigen nonspecific