Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

How regulatory T cells work

Key Points

  • Regulatory T (TReg) cells are essential for maintaining peripheral tolerance, preventing autoimmunity and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting anti-tumour immunity.

  • TReg cells have multiple mechanisms at their disposal to mediate their suppressive effects. These can be grouped into four basic 'modes of action': suppression by inhibitory cytokines, suppression by cytolysis, suppression by metabolic disruption and suppression by modulation of dendritic-cell (DC) maturation or function.

  • Suppression by inhibitory cytokines: interleukin-10 (IL-10), transforming growth factor-β (TGFβ) and the newly identified IL-35 are key mediators of TReg-cell function. Although they are all inhibitory, the extent to which they are used in distinct pathogenic or homeostatic settings differs, suggesting a non-overlapping function.

  • Suppression by cytolysis: both mouse and human TReg cells have been shown to mediate cytolysis via granzyme A and/or granzyme B and perforin in vitro and in vivo.

  • Suppression by metabolic disruption: a collection of intriguing mechanisms have recently been shown to either suppress or kill the target cell. Cytokine-deprivation-mediated apoptosis is mediated by the rapid consumption of IL-2 by CD25+ TReg cells, whereas the pericellular generation of adenosine and the intracellular transfer of cyclic AMP through membrane gap junctions expose the target cell to two potently inhibitory molecules.

  • Suppression by modulation of DC maturation or function: two mechanisms have been proposed. First, cytotoxic T-lymphocyte antigen 4 (CTLA4)–CD80/CD86 interactions induce the release of indoleamine 2,3-dioxygenase (IDO), a potent regulatory molecule, which induces the catabolism of tryptophan into pro-apoptotic metabolites. Second, lymphocyte-activation gene 3 (LAG3) binding to MHC class II molecules inhibits DC maturation and function.

  • Several complicating issues should be considered when evaluating the importance of these varied mechanisms. First, TReg-cell function is considered contact-dependent yet it is not clear how some mechanisms might mediate their function in this manner (for example, cytokines). Second, it is not clear for many of these mechanisms whether the primary target cell is the effector T cells and/or DCs or other antigen-presenting cells.

  • An important question is how many mechanisms do TReg cells need. There could be a single primary mechanism, multiple redundant mechanisms or multiple non-redundant mechanisms. Current data favour the latter but this remains to be fully defined and may vary depending on type of TReg cell involved and the context in which it is mediating its regulatory function.

  • We present the hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate TReg-cell function.

Abstract

Regulatory T (TReg) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting antitumour immunity. Given that TReg cells can have both beneficial and deleterious effects, there is considerable interest in determining their mechanisms of action. In this Review, we describe the basic mechanisms used by TReg cells to mediate suppression and discuss whether one or many of these mechanisms are likely to be crucial for TReg-cell function. In addition, we propose the hypothesis that effector T cells may not be 'innocent' parties in this suppressive process and might in fact potentiate TReg-cell function.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Basic mechanisms used by TReg cells.
Figure 2: Model for how effector T cells might boost TReg-cell function.

Similar content being viewed by others

References

  1. Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 182, 18–32 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Shevach, E. M. et al. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol. Rev. 212, 60–73 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Xystrakis, E., Boswell, S. E. & Hawrylowicz, C. M. T regulatory cells and the control of allergic disease. Expert. Opin. Biol. Ther. 6, 121–133 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Coombes, J. L., Robinson, N. J., Maloy, K. J., Uhlig, H. H. & Powrie, F. Regulatory T cells and intestinal homeostasis. Immunol. Rev. 204, 184–194 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Belkaid, Y. Regulatory T cells and infection: a dangerous necessity. Nature Rev. Immunol. 7, 875–888 (2007).

    Article  CAS  Google Scholar 

  6. Rouse, B. T., Sarangi, P. P. & Suvas, S. Regulatory T cells in virus infections. Immunol. Rev. 212, 272–286 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Kretschmer, K., Apostolou, I., Jaeckel, E., Khazaie, K. & von Boehmer, H. Making regulatory T cells with defined antigen specificity: role in autoimmunity and cancer. Immunol. Rev. 212, 163–169 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003). References 8 and 9 provided the first direct evidence that FOXP3 is required for T Reg -cell development and is sufficient to confer regulatory activity on naive T cells.

    Article  CAS  Google Scholar 

  10. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genet. 27, 20–21 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Wildin, R. S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature Genet. 27, 18–20 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genet. 27, 68–73 (2001). References 10–12 were the first to identify FOXP3 as the defective gene in patients with IPEX and in scurfy mice.

    Article  CAS  PubMed  Google Scholar 

  13. Rudensky, A. Foxp3 and dominant tolerance. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 360, 1645–1646 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ramsdell, F. Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity 19, 165–168 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Hill, J. A. et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786–800 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Allan, S. E. et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int. Immunol. 19, 345–354 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Morgan, M. E. et al. Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum. Immunol. 66, 13–20 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Wang, J., Ioan-Facsinay, A., van der Voort, E. I., Huizinga, T. W. & Toes, R. E. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur. J. Immunol. 37, 129–138 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Gavin, M. A. et al. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc. Natl Acad. Sci. USA 103, 6659–6664 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tran, D. Q., Ramsey, H. & Shevach, E. M. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-β-dependent but does not confer a regulatory phenotype. Blood 110, 2983–2990 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vignali, D. How many mechanisms do regulatory T cells need? Eur. J. Immunol. 38, 908–911 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Tang, Q. & Bluestone, J. A. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nature Immunol. 9, 239–244 (2008).

    Article  CAS  Google Scholar 

  23. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. 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. 155, 1151–1164 (1995). This seminal paper re-ignited interest in 'suppressor' cells by demonstrating that a small CD4+CD25+ T-cell population had regulatory activity.

    CAS  PubMed  Google Scholar 

  24. Shevach, E. M. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25, 195–201 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Takahashi, T. et al. 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. 10, 1969–1980 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Thornton, A. M. & Shevach, E. M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287–296 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dieckmann, D., Plottner, H., Berchtold, S., Berger, T. & Schuler, G. Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J. Exp. Med. 193, 1303–1310 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jonuleit, H. et al. Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J. Exp. Med. 193, 1285–1294 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hawrylowicz, C. M. & O'Garra, A. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nature Rev. Immunol. 5, 271–283 (2005).

    Article  CAS  Google Scholar 

  30. Annacker, O., Asseman, C., Read, S. & Powrie, F. Interleukin-10 in the regulation of T cell-induced colitis. J. Autoimmun. 20, 277–279 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Joetham, A. et al. Naturally occurring lung CD4+CD25+ T cell regulation of airway allergic responses depends on IL-10 induction of TGF-β. J. Immunol. 178, 1433–1442 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Kearley, J., Barker, J. E., Robinson, D. S. & Lloyd, C. M. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J. Exp. Med. 202, 1539–1547 (2005). This paper revealed the interesting distinction that IL-10 is required for the T Reg -cell-mediated control of airway hyper-reactivity but is derived from the suppressed effector T cells rather than the T Reg cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Stoop, J. N. et al. Tumor necrosis factor α inhibits the suppressive effect of regulatory T cells on the hepatitis B virus-specific immune response. Hepatology 46, 699–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Molitor-Dart, M. L. et al. Developmental exposure to noninherited maternal antigens induces CD4+ T regulatory cells: relevance to mechanism of heart allograft tolerance. J. Immunol. 179, 6749–6761 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Kursar, M. et al. Cutting Edge: regulatory T cells prevent efficient clearance of Mycobacterium tuberculosis. J. Immunol. 178, 2661–2665 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Jankovic, D. et al. Conventional T-bet+Foxp3 Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 204, 273–283 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Anderson, C. F., Oukka, M., Kuchroo, V. J. & Sacks, D. CD4+CD25Foxp3Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med. 204, 285–297 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Beiting, D. P. et al. Coordinated control of immunity to muscle stage Trichinella spiralis by IL-10, regulatory T cells, and TGF-β. J. Immunol. 178, 1039–1047 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999). This paper demonstrated that T Reg cells require IL-10 for their maximal regulatory activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bergmann, C., Strauss, L., Zeidler, R., Lang, S. & Whiteside, T. L. Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment. Cancer Immunol. Immunother. 56, 1429–1442 (2007).

    Article  PubMed  Google Scholar 

  42. Loser, K. et al. IL-10 controls ultraviolet-induced carcinogenesis in mice. J. Immunol. 179, 365–371 (2007).

    Article  CAS  PubMed  Google Scholar 

  43. Erhardt, A., Biburger, M., Papadopoulos, T. & Tiegs, G. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology 45, 475–485 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Ivars, F. T cell subset-specific expression of antigen receptor β chains in α chain-transgenic mice. Eur. J. Immunol. 22, 635–639 (1992).

    Article  CAS  PubMed  Google Scholar 

  45. Schumacher, A. et al. Mechanisms of action of regulatory T cells specific for paternal antigens during pregnancy. Obstet. Gynecol. 110, 1137–1145 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Mann, M. K., Maresz, K., Shriver, L. P., Tan, Y. & Dittel, B. N. B cell regulation of CD4+CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis. J. Immunol. 178, 3447–3456 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Piccirillo, C. A. et al. CD4+CD25+ regulatory T cells can mediate suppressor function in the absence of transforming growth factor β1 production and responsiveness. J. Exp. Med. 196, 237–246 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nakamura, K., Kitani, A. & Strober, W. Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor β. J. Exp. Med. 194, 629–644 (2001). This paper demonstrated that T Reg cells require cell-surface-bound TGFβ for their maximal regulatory activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Green, E. A., Gorelik, L., McGregor, C. M., Tran, E. H. & Flavell, R. A. CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-β–TGF-β receptor interactions in type 1 diabetes. Proc. Natl Acad. Sci. USA 100, 10878–10883 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Fahlen, L. et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 737–746 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li, M. O., Wan, Y. Y. & Flavell, R. A. T cell-produced transforming growth factor-b1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26, 579–591 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Strauss, L. et al. A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-β1 mediates suppression in the tumor microenvironment. Clin. Cancer Res. 13, 4345–4354 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Hilchey, S. P., De, A., Rimsza, L. M., Bankert, R. B. & Bernstein, S. H. Follicular lymphoma intratumoral CD4+CD25+GITR+ regulatory T cells potently suppress CD3/CD28-costimulated autologous and allogeneic CD8+. J. Immunol. 178, 4051–4061 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Li, H. et al. CD4+CD25+ regulatory T cells decreased the antitumor activity of cytokine-induced killer (CIK) cells of lung cancer patients. J. Clin. Immunol. 27, 317–326 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Clayton, A., Mitchell, J. P., Court, J., Mason, M. D. & Tabi, Z. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res. 67, 7458–7466 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Xia, Z. W. et al. Heme oxygenase-1 attenuates ovalbumin-induced airway inflammation by up-regulation of Foxp3 T-regulatory cells, interleukin-10, and membrane-bound transforming growth factor-β1. Am. J. Pathol. 171, 1904–1914 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ostroukhova, M. et al. Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-β. J. Clin. Invest. 116, 996–1004 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Collison, L. W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007). This paper was the first to describe the inhibitory cytokine IL-35 and its requirement for maximal T Reg -cell maximal regulatory activity.

    Article  CAS  PubMed  Google Scholar 

  59. Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Lieberman, J. The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal. Nature Rev. Immunol. 3, 361–370 (2003).

    Article  CAS  Google Scholar 

  61. Grossman, W. J. et al. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 104, 2840–2848 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. McHugh, R. S. et al. CD4+CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311–323 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Herman, A. E., Freeman, G. J., Mathis, D. & Benoist, C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J. Exp. Med. 199, 1479–1489 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gondek, D. C., Lu, L. F., Quezada, S. A., Sakaguchi, S. & Noelle, R. J. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J. Immunol. 174, 1783–1786 (2005). This paper was the first to demonstrate that T Reg cells have cytolytic capacity and regulate in a granzyme-B-dependent manner. Reference 66 subsequently showed that the granzyme-dependent lytic activity of T Reg cells was required for their regulatory activity in vivo.

    Article  CAS  PubMed  Google Scholar 

  65. Zhao, D. M., Thornton, A. M., DiPaolo, R. J. & Shevach, E. M. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood 107, 3925–3932 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cao, X. et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27, 635–646 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Ren, X. et al. Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4+CD25+ regulatory T cells. Cell Death. Differ. 14, 2076–2084 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Garin, M. I. et al. Galectin-1: a key effector of regulation meditated by CD4+CD25+ T cells. Blood 109, 2058–2065 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. de la Rosa, M., Rutz, S., Dorninger, H. & Scheffold, A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2480–2488 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Fontenot, J. D., Rasmussen, J. P., Gavin, M. A. & Rudensky, A. Y. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nature Immunol. 6, 1142–1151 (2005).

    Article  CAS  Google Scholar 

  71. Duthoit, C. T., Mekala, D. J., Alli, R. S. & Geiger, T. L. Uncoupling of IL-2 signaling from cell cycle progression in naive CD4+ T cells by regulatory CD4+CD25+ T lymphocytes. J. Immunol. 174, 155–163 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Pandiyan, P., Zheng, L., Ishihara, S., Reed, J. & Lenardo, M. J. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nature Immunol. 8, 1353–1362 (2007).

    Article  CAS  Google Scholar 

  73. Oberle, N., Eberhardt, N., Falk, C. S., Krammer, P. H. & Suri-Payer, E. Rapid suppression of cytokine transcription in human CD4+CD25 T cells by CD4+Foxp3+ regulatory T cells: independence of IL-2 consumption, TGF-β, and various inhibitors of TCR signaling. J. Immunol. 179, 3578–3587 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Borsellino, G. et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110, 1225–1232 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Kobie, J. J. et al. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine. J. Immunol. 177, 6780–6786 (2006). References 74–76 collectively revealed the ability of T Reg cells to generate the inhibitory molecule adenosine by selective expression of CD39 and CD73. Reference 79 showed that another inhibitory adenosine nucleoside, cAMP, is directly transferred into effector T cells via gap junctions.

    Article  CAS  PubMed  Google Scholar 

  77. Zarek, P. E. et al. A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111, 251–259 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Oukka, M. Interplay between pathogenic Th17 and regulatory T cells. Ann. Rheum. Dis. 66 (Suppl 3), iii87–90 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Bopp, T. et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J. Exp. Med. 204, 1303–1310 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bluestone, J. A. & Tang, Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr. Opin. Immunol. 17, 638–642 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Tang, Q. et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nature Immunol. 7, 83–92 (2006).

    Article  CAS  Google Scholar 

  82. Tadokoro, C. E. et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J. Exp. Med. 203, 505–511 (2006). References 81 and 82 revealed the importance of T Reg -cell–DC interactions as a mechanism for blocking effector-T-cell activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+ CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000). This paper demonstrated that T Reg cells require CTLA4 for their maximal regulatory activity in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Oderup, C., Cederbom, L., Makowska, A., Cilio, C. M. & Ivars, F. Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression. Immunology 118, 240–249 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Serra, P. et al. CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 19, 877–889 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nature Immunol. 4, 1206–1212 (2003). This paper shows that T Reg cells initiate the IDO-mediated catabolism of tryptophan in a CTLA4-dependent manner.

    Article  CAS  Google Scholar 

  87. Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nature Rev. Immunol. 4, 762–774 (2004).

    Article  CAS  Google Scholar 

  88. Cederbom, L., Hall, H. & Ivars, F. CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur. J. Immunol. 30, 1538–1543 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Kryczek, I. et al. Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J. Immunol. 177, 40–44 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Lewkowich, I. P. et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J. Exp. Med. 202, 1549–1561 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Houot, R., Perrot, I., Garcia, E., Durand, I. & Lebecque, S. Human CD4+CD25high regulatory T cells modulate myeloid but not plasmacytoid dendritic cells activation. J. Immunol. 176, 5293–5298 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Misra, N., Bayry, J., Lacroix-Desmazes, S., Kazatchkine, M. D. & Kaveri, S. V. Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J. Immunol. 172, 4676–4680 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Taams, L. S. et al. Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum. Immunol. 66, 222–230 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Tiemessen, M. M. et al. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc. Natl Acad. Sci. USA 104, 19446–19451 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Workman, C. J. & Vignali, D. A. A. Negative regulation of T cell homeostasis by LAG-3 (CD223). J. Immunol. 174, 688–695 (2004).

    Article  Google Scholar 

  96. Huang, C. T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503–513 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Liang, B. et al. Regulatory T cells inhibit dendritic cells by LAG-3 engagement of MHC class II. J. Immunol. 180, 5916–5926 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Baecher-Allan, C., Wolf, E. & Hafler, D. A. MHC class II expression identifies functionally distinct human regulatory T cells. J. Immunol. 176, 4622–4631 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Sarris, M., Andersen, K. G., Randow, F., Mayr, L. & Betz, A. G. Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition. Immunity 28, 402–413 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lu, L. F. et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442, 997–1002 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Kaplan, D. Autocrine secretion and the physiological concentration of cytokines. Immunol. Today 17, 303–304 (1996).

    Article  CAS  PubMed  Google Scholar 

  102. Kleinewietfeld, M. et al. CCR6 expression defines regulatory effector/memory-like cells within the CD25+CD4+ T-cell subset. Blood 105, 2877–2886 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Baecher-Allan, C., Wolf, E. & Hafler, D. A. MHC class II expression identifies functionally distinct human regulatory T cells. J. Immunol. 176, 4622–4631 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Thornton, A. M., Donovan, E. E., Piccirillo, C. A. & Shevach, E. M. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J. Immunol. 172, 6519–6523 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nature Immunol. 8, 191–197 (2007).

    Article  CAS  Google Scholar 

  106. Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329–341 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Yi, H., Zhen, Y., Jiang, L., Zheng, J. & Zhao, Y. The phenotypic characterization of naturally occurring regulatory CD4+CD25+ T cells. Cell. Mol. Immunol. 3, 189–195 (2006).

    CAS  PubMed  Google Scholar 

  108. Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693–1700 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ TReg cells. J. Exp. Med. 203, 1701–1711 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yamaguchi, T. et al. Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity 27, 145–159 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Fontenot, J. D., Dooley, J. L., Farr, A. G. & Rudensky, A. Y. Developmental regulation of Foxp3 expression during ontogeny. J. Exp. Med. 202, 901–906 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hsieh, C. S. et al. Recognition of the peripheral self by naturally arising CD25+CD4+ T cell receptors. Immunity 21, 267–277 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Izcue, A., Coombes, J. L. & Powrie, F. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol. Rev. 212, 256–271 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Roncarolo, M. G. et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212, 28–50 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Chen, W. et al. Conversion of peripheral CD4+CD25T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    Article  CAS  PubMed  Google Scholar 

  117. Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Benson, M. J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R. J. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Schambach, F., Schupp, M., Lazar, M. A. & Reiner, S. L. Activation of retinoic acid receptor-α favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur. J. Immunol. 37, 2396–2399 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. Kang, S. G., Lim, H. W., Andrisani, O. M., Broxmeyer, H. E. & Kim, C. H. Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J. Immunol. 179, 3724–3733 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Travis, M. A. et al. Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Matsumura, Y. et al. Selective expansion of Foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells. J. Immunol. 179, 2170–2179 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Pyzik, M. & Piccirillo, C. A. TGF-β1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets. J. Leukoc. Biol. 82, 335–346 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Wei, J. et al. Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells. Proc. Natl Acad. Sci. USA 104, 18169–18174 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Grossman, W. J. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589–601 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Bluestone, J. A. & Abbas, A. K. Natural versus adaptive regulatory T cells. Nature Rev. Immunol. 3, 253–257 (2003).

    Article  CAS  Google Scholar 

  128. Liu, V. C. et al. Tumor evasion of the immune system by converting CD4+CD25 T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-β. J. Immunol. 178, 2883–2892 (2007).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Randolph Noelle and Peter Ernst for granting permission to cite their unpublished observations. This work is supported by the US National Institutes of Health (NIH), the Juvenile Diabetes Research Foundation (JDRF), a Cancer Center Support CORE grant and the American Lebanese Syrian Associated Charities (ALSAC). We apologize to those authors whose work we could not cite due to space limitations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dario A. A. Vignali.

Related links

Related links

FURTHER INFORMATION

Dario Vignali's homepage

Glossary

Peripheral tolerance

The lack of self-responsiveness of mature lymphocytes in the periphery to specific antigens. These mechanisms control potentially self-reactive lymphocytes that have escaped central-tolerance mechanisms. Peripheral tolerance is associated with suppression of the production of self-reactive antibodies by B cells and inhibition of self-reactive effector T cells, such as cytotoxic T lymphocytes. The actions of regulatory T cells constitute one mechanism of peripheral tolerance.

Type 1 diabetes

A chronic autoimmune disease that is characterized by the T-cell-mediated destruction of β-cells (which secrete insulin) in the pancreas. Individuals with type 1 diabetes develop hyperglycaemia and can develop diabetes-associated complications in multiple organ systems owing to a lack of insulin.

Inflammatory bowel disease

(IBD). A T-cell-mediated inflammatory response that affects the gastrointestinal tract. There are two forms of IBD in humans; Crohn's disease, which can affect any part of the gastrointestinal tract but usually descends from the terminal ileum, and ulcerative colitis, which mainly affects the colon. In the mouse model of IBD, most of the inflammation is confined to the large intestine. The target antigen for the pathogenic T cells is unknown.

Sterilizing immunity

An immune response that leads to the complete removal of the pathogen.

Airway hyper-reactivity

Initiated by exposure to a defined stimulus that is usually tolerated by normal individuals and that causes broncho-constriction and airway infiltration of inflammatory cells in allergic individuals.

Experimental autoimmune encephalomyelitis

(EAE). An animal model of the human autoimmune disease multiple sclerosis. EAE is experimentally induced in animals by immunization with myelin or with peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

Exosomes

Small, lipid-bilayer vesicles that are released from activated cells. They comprise either plasma membrane or membrane derived from intracellular vesicles.

Notch

A transmembrane receptor involved in the pathway for direct cell–cell signalling that regulates cell-fate choice in the development of many cell lineages, and therefore is vital in the regulation of embryonic differentiation and development.

Granzymes

A family of serine proteases that are found primarily in the cytoplasmic granules of cytotoxic T lymphocytes and natural killer cells. They enter target cells through perforin pores, and cleave and activate intracellular caspases, resulting in target-cell apoptosis.

Perforin

A component of cytolytic granules that participates in the permeabilization of plasma membranes, allowing granzymes and other cytotoxic components to enter target cells.

Adenosine nucleosides

Adenosine (C10H13N5O4) is a ribonucleoside (adenine linked to ribose) that is a structural component of nucleic acids. It is also the primary molecular component of cyclic AMP (an important intracellular second messenger), AMP, ADP and ATP (a key sourse of chemical energy for many enzymatic reactions).

Ectoenzymes

Enzymes that are outside the cell membrane and therefore can cleave extracellular substrates. These are typically tethered to the outside of the cell by a transmembrane domain.

TH17 cells

(T helper 17 cells). A subset of CD4+ T helper cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-6, IL-21 and IL-23, as well as the transcription factors RORγt (retinoic-acid-receptor-related orphan receptor-γt) and STAT3 (signal transducer and activator of transcription 3).

Intravital microscopy

This is used for examination of biological processes, such as leukocyte–endothelial-cell interactions, in living tissue. In general, translucent tissues are used, such as the mesentery or cremaster muscle, which can be exposed and mounted for microscopic observation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vignali, D., Collison, L. & Workman, C. How regulatory T cells work. Nat Rev Immunol 8, 523–532 (2008). https://doi.org/10.1038/nri2343

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2343

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing