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Opinion-regulatory lymphocytes

Natural versus adaptive regulatory T cells

Nature Reviews Immunology volume 3, pages 253–257 (2003)Cite this article

Abstract

The regulation of immune responses to self-antigens is a complex process that involves maintaining self-tolerance while retaining the capacity to mount robust immune responses against invading microorganisms. Over the past few years, many new insights into this process have been gained, leading to the re-emergence of the idea that regulatory T (TReg) cells are a central mechanism of immune regulation. These insights have raised fundamental questions concerning what constitutes a TReg cell, where they develop and what signals maintain TReg-cell populations in a functional state. Here, we propose the existence of two subsets of CD4+ TReg cells — natural and adaptive — that differ in terms of their development, specificity, mechanism of action and dependence on T-cell receptor and co-stimulatory signalling.

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Figure 1: Two classes of regulatory T cells can be envisioned.
Figure 2: Model of two pathways of T-cell activation that are CD28 dependent.

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References

  1. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains. J. Immunol. 155, 1151–1164 (1995).

    CAS  PubMed  Google Scholar 

  2. Asano, M., Toda, M., Sakaguchi, N. & Sakaguchi, S. Autoimmune disease as a consequence of developmental abnormality of a T-cell subpopulation. J. Exp. Med. 184, 387–396 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Shevach, E. M. CD4+CD25+ suppressor T cells: more questions than answers. Nature Rev. Immunol. 2, 389–400 (2002).

    Article  CAS  Google Scholar 

  4. Jordan, M. S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nature Immunol. 2, 301–306 (2001).

    Article  CAS  Google Scholar 

  5. Barrat, F. J. et al. In vitro generation of interleukin-10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (TH1)- and TH2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chatenoud, L., Primo, J. & Bach, J. F. CD3 antibody-induced dominant self-tolerance in overtly diabetic NOD mice. J. Immunol. 158, 2947–2954 (1997).

    CAS  PubMed  Google Scholar 

  7. 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 

  8. Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nature Immunol. 2, 1032–1039 (2001).

    Article  CAS  Google Scholar 

  9. Salomon, B. et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12, 431–440 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nature Immunol. 3, 135–142 (2002).

    Article  CAS  Google Scholar 

  11. Malek, T. R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Seddon, B. & Mason, D. Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J. Exp. Med. 189, 877–882 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Boden, E., Tang, Q., Bour-Jordan, H. & Bluestone, J. A. in Novartis Foundation Symposium 252. Generation and Effector Functions of Regulatory Lymphocytes (Wiley, Europe) (in the press).

  14. Bensinger, S. J., Bandeira, A., Jordan, M. S., Caton, A. J. & Laufer, T. M. Major histocompatibility complex class-II-positive cortical epithelium mediates the selection of CD4+CD25+ immunoregulatory T cells. J. Exp. Med. 194, 427–438 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lenschow, D. et al. CD28/B7 regulation of TH1 and TH2 subsets in the development of autoimmune diabetes. Immunity 5, 285–293 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Sharif, S. et al. Activation of natural killer T cells by α-galactosylceramide treatment prevents the onset and recurrence of autoimmune type 1 diabetes. Nature Med. 7, 1057–1062 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Bach, J. F. Regulatory T cells under scrutiny. Nature Rev. Immunol. 3, 189–198 (2003).

    Article  Google Scholar 

  18. Maloy, K. J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nature Immunol. 2, 816–822 (2001).

    Article  CAS  Google Scholar 

  19. Kingsley, C. I., Karim, M., Bushell, A. R. & Wood, K. J. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J. Immunol. 168, 1080–1086 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen, Y., Kuchroo, V. K., Inobe, J. -I., Hafler, D. A. & Weiner, H. L. Regulatory T-cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Levings, M. K., Sangregorio, R. & Roncarolo, M. -G. Human CD25+CD4+ T cells suppress naive and memory T-cell proliferation and can be expanded in vitro without loss of suppressor function. J. Exp. Med. 193, 1295–1302 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gonzalez, A., Andre-Schmutz, I., Carnaud, C., Mathis, D. & Benoist, C. Damage control, rather than unresponsiveness, effected by protective DX5+ T cells in autoimmune diabetes. Nature Immunol. 2, 1117–1125 (2001).

    Article  CAS  Google Scholar 

  24. Chatenoud, L., Salomon, B. & Bluestone, J. A. Suppressor T cells — they're back and critical for regulation of autoimmunity! Immunol. Rev. 182, 149–163 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Khanna, A., Kapur, S., Sharma, V., Li, B. & Suthanthiran, M. In vivohyperexpression of transforming growth factor-β1 in mice: stimulation by cyclosporine. Transplantation 63, 1037–1039 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Apostolou, I., Sarukhan, A., Klein, L. & von Boehmer, H. Origin of regulatory T cells with known specificity for antigen. Nature Immunol. 3, 756–763 (2002).

    Article  CAS  Google Scholar 

  27. Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. M. & Sacks, D. L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Fuss, I. J., Boirivant, M., Lacy, B. & Strober, W. The interrelated roles of TGF-β and IL-10 in the regulation of experimental colitis. J. Immunol. 168, 900–908 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Powrie, F. in Novartis Foundation Symposium 252. Generation and Effector Functions of Regulatory Lymphocytes (Wiley, Europe) (in the press).

  30. Taylor, P. A., Friedman, T. M., Korngold, R., Noelle, R. J. & Blazar, B. R. Tolerance induction of alloreactive T cells via ex vivo blockade of the CD40–CD40L costimulatory pathway results in the generation of a potent immune regulatory cell. Blood 99, 4601–4609 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Furtado, G. C., de Lafaille, M. A., Kutchukhidze, N. & Lafaille, J. J. Interleukin-2 signaling is required for CD4+ regulatory T-cell function. J. Exp. Med. 196, 851–857 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bach, J. F. & Chatenoud, L. Tolerance to islet autoantigens and type I diabetes. Annu. Rev. Immunol. 19, 131–161 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Jonuleit, H. et al. Infectious tolerance: human CD25+ regulatory T cells convey suppressor activity to conventional CD4+ T helper cells. J. Exp. Med. 196, 255–260 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dieckmann, D., Bruett, C. H., Ploettner, H., Lutz, M. B. & Schuler, G. Human CD4+CD25+ regulatory, contact-dependent T cells induce interleukin-10-producing, contact-independent type-1-like regulatory T cells. J. Exp. Med. 196, 247–253 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kukreja, A. et al. Multiple immuno-regulatory defects in type-1 diabetes. J. Clin. Invest. 109, 131–140 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Inaba, K. et al. Expression of B7 costimulator molecules on mouse dendritic cells. Adv. Exp. Med. Biol. 378, 65–70 (1995).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank L. Chatenoud and J. F. Bach for helpful discussions and sharing of unpublished data.

Author information

Authors and Affiliations

  1. the Diabetes Research Center, University of California, San Francisco, 94118, California, USA

    Jeffrey A. Bluestone

  2. the Department of Pathology, University of California, San Francisco, USA

    Abul K. Abbas

Authors
  1. Jeffrey A. Bluestone
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  2. Abul K. Abbas
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Corresponding author

Correspondence to Jeffrey A. Bluestone.

Related links

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DATABASES

LocusLink

BCL-XL

CD25

CD28

CD38

CD62L

CD80

CD86

CD103

CTLA4

GITR

IL-2

IL-10

IL-15

IL-15R

OX40

TGF-β

OMIM

multiple sclerosis

type 1 diabetes

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Bluestone, J., Abbas, A. Natural versus adaptive regulatory T cells. Nat Rev Immunol 3, 253–257 (2003). https://doi.org/10.1038/nri1032

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