Trends in Molecular Medicine
ReviewNatural regulatory T cells: mechanisms of suppression
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 CD25highCD4+ 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 CD25highCD4+ 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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