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:

Natural regulatory T cells in infectious disease

Abstract

This review discusses the control exerted by natural CD4+ CD25+ regulatory T cells (natural Treg cells) during infectious processes. Natural Treg cells may limit the magnitude of effector responses, which may result in failure to adequately control infection. However, natural Treg cells also help limit collateral tissue damage caused by vigorous antimicrobial immune responses. We describe here various situations in which the balance between natural Treg cells and effector immune functions influences the outcome of infection and discuss how manipulating this equilibrium might be exploited therapeutically.

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: Function and localization of natural Treg cells during infections.
Figure 2: Manipulation of natural Treg cells as a therapeutic approach during infection.

Similar content being viewed by others

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 (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Piccirillo, C.A. & Shevach, E.M. Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin. Immunol. 16, 81–88 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Mills, K.H. & McGuirk, P. Antigen-specific regulatory T cells–their induction and role in infection. Semin. Immunol. 16, 107–117 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. O'Garra, A., Vieira, P.L., Vieira, P. & Goldfeld, A.E. IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage. J. Clin. Invest. 114, 1372–1378 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fontenot, J.D. & Rudensky, A. A well adapted regulatory contrivance: regulatory T cell development and the Forkhead family transcription factor Foxp3. Nat. Immunol. 6, 331–337 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Powrie, F., Read, S., Mottet, C., Uhlig, H. & Maloy, K. Control of immune pathology by regulatory T cells. Novartis Found. Symp. 252, 92–8 (2003).

    CAS  PubMed  Google Scholar 

  8. Kullberg, M.C. et al. Bacteria-triggered CD4+ T regulatory cells suppress Helicobacter hepaticus-induced colitis. J. Exp. Med. 196, 505–515 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Maloy, K.J.S.L., Cahill, R, Dougan G, Saunders NJ, Powrie F. CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Maloy, K.J. et al. CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Raghavan, S., Fredriksson, M., Svennerholm, A.M., Holmgren, J. & Suri-Payer, E. Absence of CD4+CD25+ regulatory T cells is associated with a loss of regulation leading to increased pathology in Helicobacter pylori-infected mice. Clin. Exp. Immunol. 132, 393–400 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lundgren, A., Suri-Payer, E., Enarsson, K., Svennerholm, A.M. & Lundin, B.S. Helicobacter pylori-specific CD4+ CD25high regulatory T cells suppress memory T-cell responses to H. pylori in infected individuals. Infect. Immun. 71, 1755–1762 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hori, S., Carvalho, T.L. & Demengeot, J. CD25+CD4+ regulatory T cells suppress CD4+ T cell-mediated pulmonary hyperinflammation driven by Pneumocystis carinii in immunodeficient mice. Eur. J. Immunol. 32, 1282–1291 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Montagnoli, C. et al. B7/CD28-dependent CD4+CD25+ regulatory T cells are essential components of the memory-protective immunity to Candida albicans. J. Immunol. 169, 6298–6308 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Sacks, D. & Noben-Trauth, N. The immunology of susceptibility and resistance to Leishmania major in mice. Nat. Rev. Immunol. 2, 845–858 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Aseffa, A. et al. The early IL-4 response to Leishmania major and the resulting Th2 cell maturation steering progressive disease in BALB/c mice are subject to the control of regulatory CD4+CD25+ T cells. J. Immunol. 169, 3232–3241 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Xu, D.L.H., Komai-Koma M, Campbell C, McSharry C, Alexander J, Liew FY. CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, Leishmania major infection, and colitis in mice. J. Immunol. 170, 394–399 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Liu, H., Hu, B., Xu, D. & Liew, F.Y. CD4+CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-β, and CTLA4. J. Immunol. 171, 5012–5017 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. McKee, A.S. & Pearce, E.J. CD25+CD4+ cells contribute to Th2 polarization during helminth infection by suppressing Th1 response development. J. Immunol. 173, 1224–1231 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Hesse, M. et al. The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells. J. Immunol. 172, 3157–3166 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Cabrera, R. et al. An immunomodulatory role for CD4+CD25+ regulatory T lymphocytes in hepatitis C virus infection. Hepatology 40, 1062–1071 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Suvas, S., Azkur, A.K., Kim, B.S., Kumaraguru, U. & Rouse, B.T. CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. J. Immunol. 172, 4123–4132 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Belkaid, Y. et al. A natural model of Leishmania major infection reveals a prolonged 'silent' phase of parasite amplification in the skin before the onset of lesion formation and immunity. J. Immunol. 165, 969–977 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Good, M.F., Xu, H., Wykes, M. & Engwerda, C.R. Development and regulation of cell-mediated immune responses to the blood stages of malaria: implications for vaccine research. Annu. Rev. Immunol. (in the press).

  26. Hisaeda, H. et al. Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells. Nat. Med. 10, 29–30 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Long, T.T., Nakazawa, S., Onizuka, S., Huaman, M.C. & Kanbara, H. Influence of CD4+CD25+ T cells on Plasmodium berghei NK65 infection in BALB/c mice. Int. J. Parasitol. 33, 175–183 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Suvas, S., Kumaraguru, U., Pack, C.D., Lee, S. & Rouse, B.T. CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J. Exp. Med. 198, 889–901 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Iwashiro, M. et al. Immunosuppression by CD4+ regulatory T cells induced by chronic retroviral infection. Proc. Natl. Acad. Sci. USA 98, 9226–9230 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dittmer, U. et al. Functional impairment of CD8+ T cells by regulatory T cells during persistent retroviral infection. Immunity 20, 293–303 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Beilharz, M.W. et al. Timed ablation of regulatory CD4+ T cells can prevent murine AIDS progression. J. Immunol. 172, 4917–4925 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Aandahl, E.M., Michaelsson, J., Moretto, W.J., Hecht, F.M. & Nixon, D.F. Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens. J. Virol. 78, 2454–2459 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kinter, A.L. et al. CD25+CD4+ regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4+ and CD8+ HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J. Exp. Med. 200, 331–343 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Weiss, L. et al. Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood 104, 3249–3256 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Sugimoto, K. et al. Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection. Hepatology 38, 1437–1448 (2003).

    PubMed  Google Scholar 

  36. Boyer, O. et al. CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. Blood 103, 3428–3430 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Mendez, S., Reckling, S.K., Piccirillo, C.A., Sacks, D. & Belkaid, Y. Role for CD4+ CD25+ regulatory T cells in reactivation of persistent leishmaniasis and control of concomitant immunity. J. Exp. Med. 200, 201–210 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kursar, M. et al. Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses. J. Exp. Med. 196, 1585–1592 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Toka, F., Suvas, S. & Rouse, B.T. CD4+/CD25+ T cells regulate vaccine generated primary and memory CD8+ T cell responses against herpes simplex virus. J. Virol. 78, 13082–13089 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rajagopalan, S. Tuberculosis and aging: a global health problem. Clin. Infect. Dis. 33, 1034–1039 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Gane, E. & Pilmore, H. Management of chronic viral hepatitis before and after renal transplantation. Transplantation 74, 427–437 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Walker, L.S., Chodos, A., Eggena, M., Dooms, H. & Abbas, A.K. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J. Exp. Med. 198, 249–258 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Klein, L., Khazaie, K. & von Boehmer, H. In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc. Natl. Acad. Sci. USA 100, 8886–8891 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hori, S., Haury, M., Lafaille, J.J., Demengeot, J. & Coutinho, A. Peripheral expansion of thymus-derived regulatory cells in anti-myelin basic protein T cell receptor transgenic mice. Eur. J. Immunol. 32, 3729–3735 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  46. Pawelec, G. et al. Is human immunosenescence clinically relevant? Looking for 'immunological risk phenotypes'. Trends Immunol. 23, 330–332 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Shimizu, J. & Moriizumi, E. Aging-dependent generation of suppressive CD4+CD25R123loCD103+ T cells in mice. Eur. J. Immunol. 33, 2449–2458 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Shimizu, J. & Moriizumi, E. CD4+CD25- T cells in aged mice are hyporesponsive and exhibit suppressive activity. J. Immunol. 170, 1675–1682 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Raghavan, S., Suri-Payer, E. & Holmgren, J. Antigen-specific in vitro suppression of murine Helicobacter pylori-reactive immunopathological T cells by CD4CD25 regulatory T cells. Scand. J. Immunol. 60, 82–88 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. MacDonald, A.J. et al. CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J. Infect. Dis. 185, 720–727 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Wucherpfennig, K.W. & Strominger, J.L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. von Herrath, M.G., Evans, C.F., Horwitz, M.S. & Oldstone, M.B. Using transgenic mouse models to dissect the pathogenesis of virus-induced autoimmune disorders of the islets of Langerhans and the central nervous system. Immunol. Rev. 152, 111–143 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Rouse, B.T. & Deshpande, S. Viruses and autoimmunity: an affair but not a marriage contract. Rev. Med. Virol. 12, 107–113 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  54. de Oliveira, M.R. et al. Influence of microbiota in experimental cutaneous leishmaniasis in Swiss mice. Rev. Inst. Med. Trop. Sao Paulo 41, 87–94 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Singer, S.M. & Nash, T.E. The role of normal flora in Giardia lamblia infections in mice. J. Infect. Dis. 181, 1510–1512 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Joshi, A., Vahlenkamp, T.W., Garg, H., Tompkins, W.A. & Tompkins, M.B. Preferential replication of FIV in activated CD4+CD25+ T cells independent of cellular proliferation. Virology 321, 307–322 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Caramalho, I. et al. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J. Exp. Med. 197, 403–411 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yamazaki, S. et al. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J. Exp. Med. 198, 235–247 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Oswald-Richter, K. et al. HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells. PLoS Biol. 7, 955–966 (2004).

    Google Scholar 

  60. Andersson, J. et al. Cutting edge: the prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients. J. Immunol. 174, 3143–3147 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zheng, S.G., Wang, J.H., Gray, J.D., Soucier, H. & Horwitz, D.A. Natural and induced CD4+CD25+ cells educate CD4+CD25 cells to develop suppressive activity: the role of IL-2, TGF-γ, and IL-10. J. Immunol. 172, 5213–5221 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Bystry, R.S., Aluvihare, V., Welch, K.A., Kallikourdis, M. & Betz, A.G. B cells and professional APCs recruit regulatory T cells via CCL4. Nat. Immunol. 2, 1126–1132 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Iellem, A. et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4+CD25+ regulatory T cells. J. Exp. Med. 194, 847–853 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Szanya, V., Ermann, J., Taylor, C., Holness, C. & Fathman, C.G. The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. J. Immunol. 169, 2461–2465 (2002).

    Article  CAS  PubMed  Google Scholar 

  67. Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science [comment] 299, 1033–1036 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Choi, B.K. et al. 4–1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells. J. Leukoc. Biol. 75, 785–791 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. 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 

  70. Gangappa, S., Manickan, E. & Rouse, B.T. Control of herpetic stromal keratitis using CTLA4Ig fusion protein. Clin. Immunol. Immunopathol. 86, 88–94 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Belkaid, Y. et al. The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J. Exp. Med. 194, 1497–1506 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Murphy, M.L., Cotterell, S.E., Gorak, P.M., Engwerda, C.R. & Kaye, P.M. Blockade of CTLA-4 enhances host resistance to the intracellular pathogen, Leishmania donovani. J. Immunol. 161, 4153–4160 (1998).

    CAS  PubMed  Google Scholar 

  73. 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 

  74. Stephens, G.L. et al. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J. Immunol. 173, 5008–5020 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. He, H. et al. Reduction of retrovirus-induced immunosuppression by in vivo modulation of T cells during acute infection. J. Virol. 78, 11641–11647 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mottet, C., Uhlig, H.H. & Powrie, F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J. Immunol. 170, 3939–3943 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Belghith, M. et al. TGF-β-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat. Med. 9, 1202–1208 (2003).

    Article  CAS  PubMed  Google Scholar 

  78. Taylor, P.A., Lees, C.J. & Blazar, B.R. The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99, 3493–3499 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. 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 

  80. Netea, M.G. et al. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J. Immunol. 172, 3712–3718 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Vahlenkamp, T.W., Tompkins, M.B. & Tompkins, W.A. Feline immunodeficiency virus infection phenotypically and functionally activates immunosuppressive CD4+CD25+ T regulatory cells. J. Immunol. 172, 4752–4761 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank C.L. Karp and S. Suvas for critical reading of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yasmine Belkaid.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Belkaid, Y., Rouse, B. Natural regulatory T cells in infectious disease. Nat Immunol 6, 353–360 (2005). https://doi.org/10.1038/ni1181

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1181

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