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.

Regulatory T cells and infection: a dangerous necessity

Key Points

  • Several types of regulatory T cell have been described on the basis of their origin, generation and mechanism of action, with two main subsets identified: natural regulatory T (TReg) cells, which mainly develop in the thymus and regulate self-reactive T cells in the periphery, and inducible regulatory T cells, which develop in the periphery from conventional CD4+ T cells.

  • In some infections, natural TReg cells mediate a compromise between the host and the pathogen by favouring pathogen expansion and persistence while limiting immunopathology.

  • The nature of the antigens recognized by natural TReg cells during infection is not well understood. During the onset of acute infection, natural TReg cells could recognize self antigens that are released by tissue damage; however, during chronic infection, evidence suggests that natural TReg cells recognize microbial antigens.

  • During various infections, interleukin-10 (IL-10)-producing T regulatory 1 (TR1) cells develop from conventional T cells after encounter with certain signals, such as exposure to deactivated or immature antigen-presenting cells, repeated exposure to antigen, exposure to microbial products or IL-10 itself.

  • CD4+ T cells that produce both interferon-γ (IFNγ) and IL-10 also can emerge during certain experimental infections and have an important role in the control of T helper 1 (TH1)-cell-mediated immunopathology.

  • Recent evidence supports the idea that infection-induced regulatory T cells can have a major role in the outcome of secondary infections, as well as in autoimmune or allergic responses.

  • Microorganisms themselves can promote the emergence, survival, recruitment or function of TReg cells to favour their own survival.

  • In some circumstances, the regulation exerted by regulatory T cells is excessive and therefore prevents the establishment of protective immune responses, whereas in other circumstances, this control is not sufficient to prevent immunopathology. At both extremes, manipulation of regulatory T cells could offer therapeutic potential.

Abstract

Surviving a given infection requires the generation of a controlled immune response. Failure to establish or restore homeostatic conditions during or following the onset of an infection can lead to tissue damage. Investigation of the immunoregulatory network that arises in response to the infectious process or that is induced by the pathogen itself should provide insight into therapeutic approaches for the control of infection and any subsequent immunopathology. In this Review, I discuss current hypotheses and points of polemic associated with the origin, mode of action and antigen specificity of the various populations of regulatory T cells that arise during infection.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Regulatory T cells during infection.
Figure 2: The nature of regulatory T cells involved and the mechanism of suppression depend on the strength and stage of the pathological process.
Figure 3: Origin and specificity of natural regulatory T cells during infections.
Figure 4: Positive and negative roles of regulatory T cells during infection.
Figure 5: Potential strategies used by pathogens to promote regulatory T-cell induction and functions.

References

  1. Sacks, D. & Sher, A. Evasion of innate immunity by parasitic protozoa. Nature Immunol. 3, 1041–1047 (2002).

    CAS  Article  Google Scholar 

  2. Mahanty, S. et al. High levels of spontaneous and parasite antigen-driven interleukin-10 production are associated with antigen-specific hyporesponsiveness in human lymphatic filariasis. J. Infect. Dis. 173, 769–773 (1996).

    CAS  PubMed  Article  Google Scholar 

  3. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 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 

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

    CAS  PubMed  Article  Google Scholar 

  6. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  9. von Boehmer, H. Mechanisms of suppression by suppressor T cells. Nature Immunol. 6, 338–344 (2005).

    CAS  Article  Google Scholar 

  10. Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nature Immunol. 4, 1206–1212 (2003).

    CAS  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Powrie, F., Read, S., Mottet, C., Uhlig, H. & Maloy, K. Control of immune pathology by regulatory T cells. Novartis Found. Symp. 252, 92–98 (2003).

    CAS  PubMed  Google Scholar 

  13. 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).

    CAS  PubMed  Article  Google Scholar 

  14. 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).

    CAS  PubMed  Article  Google Scholar 

  15. 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). This study was the first to demonstrate that natural T Reg cells accumulate at sites of infection and mediate microbial persistence while maintaining immunity to re-infection.

    CAS  PubMed  Article  Google Scholar 

  16. Hisaeda, H. et al. Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells. Nature Med. 10, 29–30 (2004). This study was the first to demonstrate that natural T Reg cells can excessively limit effector responses and thereby lead to death of the host.

    CAS  PubMed  Article  Google Scholar 

  17. Taylor, M. D. et al. Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo. J. Immunol. 174, 4924–4933 (2005).

    CAS  PubMed  Article  Google Scholar 

  18. Walther, M. et al. Upregulation of TGF-β, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23, 287–296 (2005). This study carried out in human volunteers documents the expansion of FOXP3+ T cells during the first days of infection with the causal agent of malaria. It shows a positive correlation between FOXP3+ T-cell expansion and TGFβ levels.

    CAS  PubMed  Article  Google Scholar 

  19. Andersson, J. et al. The prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients. J. Immunol. 174, 3143–3147 (2005). This study shows that FOXP3+ T cells accumulate in the lymphoid tissues of patients infected with HIV.

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  21. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  23. Kornfeld, C. et al. Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS. J. Clin. Invest. 115, 1082–1091 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Epple, H. J. et al. Mucosal but not peripheral FOXP3+ regulatory T cells are highly increased in untreated HIV infection and normalize after suppressive HAART. Blood 108, 3072–3078 (2006).

    CAS  PubMed  Article  Google Scholar 

  25. Pereira, L. E. et al. Simian immunodeficiency virus (SIV) infection influences the level and function of regulatory T cells in SIV-infected rhesus macaques but not SIV-infected sooty mangabeys. J. Virol. 81, 4445–4456 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Xu, D. et al. Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J. Immunol. 177, 739–747 (2006).

    CAS  PubMed  Article  Google Scholar 

  27. 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 

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

    CAS  Article  PubMed  Google Scholar 

  29. Bolacchi, F. et al. Increased hepatitis C virus (HCV)-specific CD4+CD25+ regulatory T lymphocytes and reduced HCV-specific CD4+ T cell response in HCV-infected patients with normal versus abnormal alanine aminotransferase levels. Clin. Exp. Immunol. 144, 188–196 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  32. 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).

    CAS  PubMed  Article  Google Scholar 

  33. Hisaeda, H. et al. Resistance of regulatory T cells to glucocorticoid-induced TNFR family-related protein (GITR) during Plasmodium yoelii infection. Eur. J. Immunol. 35, 3516–3524 (2005).

    CAS  PubMed  Article  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). This study shows that the removal of natural T Reg cells from peripheral-blood mononuclear cells of HIV-infected patients reveals antigen-specific responses against HIV.

    CAS  PubMed  Article  Google Scholar 

  35. 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).

    CAS  Article  PubMed  Google Scholar 

  36. Suffia, I. J., Reckling, S. K., Piccirillo, C. A., Goldszmid, R. S. & Belkaid, Y. Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. J. Exp. Med. 203, 777–788 (2006). This study shows that natural T Reg cells can also recognize microbial antigens.

    CAS  PubMed  PubMed Central  Article  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    CAS  PubMed  Article  Google Scholar 

  39. Hoffmann, K. F., Cheever, A. W. & Wynn, T. A. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J. Immunol. 164, 6406–6416 (2000).

    CAS  PubMed  Article  Google Scholar 

  40. Gazzinelli, R. T., Oswald, I. P., James, S. L. & Sher, A. IL-10 inhibits parasite killing and nitrogen oxide production by IFN-γ-activated macrophages. J. Immunol. 148, 1792–1796 (1992).

    CAS  PubMed  Google Scholar 

  41. Li, C., Corraliza, I. & Langhorne, J. A defect in interleukin-10 leads to enhanced malarial disease in Plasmodium chabaudi chabaudi infection in mice. Infect. Immun. 67, 4435–4442 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Plebanski, M. et al. Interleukin 10-mediated immunosuppression by a variant CD4 T cell epitope of Plasmodium falciparum. Immunity 10, 651–660 (1999).

    CAS  PubMed  Article  Google Scholar 

  43. Boussiotis, V. A. et al. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J. Clin. Invest. 105, 1317–1325 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Mahanty, S. et al. Regulation of parasite antigen-driven immune responses by interleukin-10 (IL-10) and IL-12 in lymphatic filariasis. Infect. Immun. 65, 1742–1747 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Carvalho, E. M. et al. Restoration of IFN-γ production and lymphocyte proliferation in visceral leishmaniasis. J. Immunol. 152, 5949–5956 (1994).

    CAS  PubMed  Google Scholar 

  46. King, C. L. et al. Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity. J. Immunol. 156, 4715–4721 (1996).

    CAS  PubMed  Google Scholar 

  47. Gazzinelli, R. T. et al. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-γ and TNF-α. J. Immunol. 157, 798–805 (1996). This study, together with reference 37, indicates the paradoxical effect of IL-10. In the absence of this regulatory cytokine, the host can efficiently control microbial infection but dies because of uncontrolled immune responses.

    CAS  PubMed  Google Scholar 

  48. Ramalingam, T. R., Reiman, R. M. & Wynn, T. A. Exploiting worm and allergy models to understand Th2 cytokine biology. Curr. Opin. Allergy Clin. Immunol. 5, 392–398 (2005).

    CAS  PubMed  Article  Google Scholar 

  49. Miles, S. A., Conrad, S. M., Alves, R. G., Jeronimo, S. M. & Mosser, D. M. A role for IgG immune complexes during infection with the intracellular pathogen Leishmania. J. Exp. Med. 201, 747–754 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  51. McGuirk, P., McCann, C. & Mills, K. H. Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J. Exp. Med. 195, 221–231 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Van der Kleij, D. et al. Triggering of innate immune responses by schistosome egg glycolipids and their carbohydrate epitope GalNAcβ1–4(Fucα1–2Fucα1–3) GlcNAc. J. Infect. Dis. 185, 531–539 (2002). References 51 and 52 identify microbial products that can specifically induce IL-10-producing T cells with regulatory properties.

    CAS  PubMed  Article  Google Scholar 

  53. Marshall, N. A., Vickers, M. A. & Barker, R. N. Regulatory T cells secreting IL-10 dominate the immune response to EBV latent membrane protein 1. J. Immunol. 170, 6183–6189 (2003).

    CAS  PubMed  Article  Google Scholar 

  54. Marshall, N. A. et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103, 1755–1762 (2004).

    CAS  PubMed  Article  Google Scholar 

  55. Del Prete, G. et al. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J. Immunol. 150, 353–360 (1993).

    CAS  PubMed  Google Scholar 

  56. Gerosa, F. et al. CD4+ T cell clones producing both interferon-γ and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin. Immunol. 92, 224–234 (1999).

    CAS  PubMed  Article  Google Scholar 

  57. Pohl-Koppe, A., Balashov, K. E., Steere, A. C., Logigian, E. L. & Hafler, D. A. Identification of a T cell subset capable of both IFN-γ and IL-10 secretion in patients with chronic Borrelia burgdorferi infection. J. Immunol. 160, 1804–1810 (1998).

    CAS  PubMed  Google Scholar 

  58. Trinchieri, G. Regulatory role of T cells producing both interferon γ and interleukin 10 in persistent infection. J. Exp. Med. 194, F53–F57 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Anderson, C. F., Oukka, M., Kuchroo, V. J. & Sacks, D. CD4+CD25Foxp3 Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med. 204, 285–297 (2007). References 59 and 60 demonstrate that during some microbial infections, highly polarized T H 1 cells that produce IL-10 have regulatory properties.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Fantini, M. C. et al. Cutting edge: TGF-β induces a regulatory phenotype in CD4+CD25 T cells through Foxp3 induction and down-regulation of Smad7. J. Immunol. 172, 5149–5153 (2004).

    CAS  PubMed  Article  Google Scholar 

  63. Park, H. B., Paik, D. J., Jang, E., Hong, S. & Youn, J. Acquisition of anergic and suppressive activities in transforming growth factor-β-costimulated CD4+CD25 T cells. Int. Immunol. 16, 1203–1213 (2004).

    CAS  PubMed  Article  Google Scholar 

  64. Wan, Y. Y. & Flavell, R. A. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc. Natl Acad. Sci. USA 102, 5126–5131 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Kretschmer, K. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nature Immunol. 6, 1219–1227 (2005).

    CAS  Article  Google Scholar 

  67. Barnard, J. A., Warwick, G. J. & Gold, L. I. Localization of transforming growth factor β isoforms in the normal murine small intestine and colon. Gastroenterology 105, 67–73 (1993).

    CAS  PubMed  Article  Google Scholar 

  68. Mennechet, F. J. et al. Intestinal intraepithelial lymphocytes prevent pathogen-driven inflammation and regulate the Smad/T-bet pathway of lamina propria CD4+ T cells. Eur. J. Immunol. 34, 1059–1067 (2004).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  70. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Montagnoli, C. et al. Immunity and tolerance to Aspergillus involve functionally distinct regulatory T cells and tryptophan catabolism. J. Immunol. 176, 1712–1723 (2006).

    CAS  PubMed  Article  Google Scholar 

  72. Spiegel, A., Tall, A., Raphenon, G., Trape, J. F. & Druilhe, P. Increased frequency of malaria attacks in subjects co-infected by intestinal worms and Plasmodium falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 97, 198–199 (2003).

    PubMed  Article  Google Scholar 

  73. La Flamme, A. C., Ruddenklau, K. & Backstrom, B. T. Schistosomiasis decreases central nervous system inflammation and alters the progression of experimental autoimmune encephalomyelitis. Infect. Immun. 71, 4996–5004 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Zaccone, P. et al. Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes. Eur. J. Immunol. 33, 1439–1449 (2003).

    CAS  PubMed  Article  Google Scholar 

  75. Elliott, D. E. et al. Exposure to schistosome eggs protects mice from TNBS-induced colitis. Am. J. Physiol. Gastrointest Liver Physiol. 284, G385–G391 (2003).

    CAS  PubMed  Article  Google Scholar 

  76. Wilson, M. S. & Maizels, R. M. Regulatory T cells induced by parasites and the modulation of allergic responses. Chem. Immunol. Allergy 90, 176–195 (2006).

    CAS  PubMed  Google Scholar 

  77. Correale, J. & Farez, M. Association between parasite infection and immune responses in multiple sclerosis. Ann. Neurol. 61, 97–108 (2007). This work suggests that regulatory T cells that are induced during helminth infection in humans can have a protective effect against autoimmune disorders.

    CAS  PubMed  Article  Google Scholar 

  78. Wills-Karp, M., Santeliz, J. & Karp, C. L. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nature Rev. Immunol. 1, 69–75 (2001).

    CAS  Article  Google Scholar 

  79. Maizels, R. M. Infections and allergy — helminths, hygiene and host immune regulation. Curr. Opin. Immunol. 17, 656–661 (2005).

    CAS  PubMed  Article  Google Scholar 

  80. Wilson, M. S. et al. Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J. Exp. Med. 202, 1199–1212 (2005). This study shows that T Reg cells activated during helminth infections protect from excessive immune responses in an experimental model of asthma.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Di Giacinto, C., Marinaro, M., Sanchez, M., Strober, W. & Boirivant, M. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-β-bearing regulatory cells. J. Immunol. 174, 3237–3246 (2005).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  84. Enarsson, K. et al. Function and recruitment of mucosal regulatory T cells in human chronic Helicobacter pylori infection and gastric adenocarcinoma. Clin. Immunol. 121, 358–368 (2006).

    CAS  PubMed  Article  Google Scholar 

  85. Sutmuller, R. P. et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J. Clin. Invest. 116, 485–494 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Crellin, N. K. et al. Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J. Immunol. 175, 8051–8059 (2005).

    CAS  PubMed  Article  Google Scholar 

  87. Sutmuller, R. P., Morgan, M. E., Netea, M. G., Grauer, O. & Adema, G. J. Toll-like receptors on regulatory T cells: expanding immune regulation. Trends Immunol. 27, 387–393 (2006).

    CAS  PubMed  Article  Google Scholar 

  88. Liu, H., Komai-Koma, M., Xu, D. & Liew, F. Y. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc. Natl Acad. Sci. USA 103, 7048–7053 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 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).

    CAS  PubMed  Article  Google Scholar 

  90. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Nilsson, J. et al. HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS. Blood 108, 3808–3817 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Grant, C. et al. Foxp3 represses retroviral transcription by targeting both NF-κB and CREB pathways. PLoS Pathog. 2, e33 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Zaunders, J. J. et al. Infection of CD127+ (interleukin-7 receptor+) CD4+ cells and overexpression of CTLA-4 are linked to loss of antigen-specific CD4 T cells during primary human immunodeficiency virus type 1 infection. J. Virol. 80, 10162–10172 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Suffia, I., Reckling, S. K., Salay, G. & Belkaid, Y. A role for CD103 in the retention of CD4+CD25+ TReg and control of Leishmania major infection. J. Immunol. 174, 5444–5455 (2005).

    CAS  PubMed  Article  Google Scholar 

  95. Yurchenko, E. et al. CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistence. J. Exp. Med. 203, 2451–2460 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. Sebastiani, S. et al. Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity. J. Immunol. 166, 996–1002 (2001).

    CAS  PubMed  Article  Google Scholar 

  97. Freeman, C. M. et al. CCR8 is expressed by antigen-elicited, IL-10-producing CD4+CD25+ T cells, which regulate Th2-mediated granuloma formation in mice. J. Immunol. 174, 1962–1970 (2005).

    CAS  PubMed  Article  Google Scholar 

  98. Belkaid, Y. & Rouse, B. T. Natural regulatory T cells in infectious disease. Nature Immunol. 6, 353–360 (2005).

    CAS  Article  Google Scholar 

  99. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 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).

    CAS  PubMed  Article  Google Scholar 

  101. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 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).

    CAS  Article  Google Scholar 

  103. Sather, B. D. et al. Altering the distribution of Foxp3+ regulatory T cells results in tissue-specific inflammatory disease. J. Exp. Med. 204, 1335–1347 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Manigold, T. et al. Foxp3+CD4+CD25+ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C. Blood 107, 4424–4432 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 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 type 1. J. Virol. 78, 13082–13089 (2004). This work demonstrates that limiting T Reg -cell function can enhance the efficiency of vaccines against microbial infections.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Furuichi, Y. et al. Depletion of CD25+CD4+T cells (Tregs) enhances the HBV-specific CD8+ T cell response primed by DNA immunization. World J. Gastroenterol. 11, 3772–3777 (2005).

    PubMed  PubMed Central  Article  Google Scholar 

  108. Moore, A. C. et al. Anti-CD25 antibody enhancement of vaccine-induced immunogenicity: increased durable cellular immunity with reduced immunodominance. J. Immunol. 175, 7264–7273 (2005).

    CAS  PubMed  Article  Google Scholar 

  109. Haeryfar, S. M., DiPaolo, R. J., Tscharke, D. C., Bennink, J. R. & Yewdell, J. W. Regulatory T cells suppress CD8+ T cell responses induced by direct priming and cross-priming and moderate immunodominance disparities. J. Immunol. 174, 3344–3351 (2005). References 108 and 109 show that limiting regulatory T cells at the time of vaccination can favour responses to subdominant antigens.

    CAS  PubMed  Article  Google Scholar 

  110. Shaw, M. H. et al. Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-γ-dependent IL-10 reactivation. J. Immunol. 176, 7263–7271 (2006).

    CAS  PubMed  Article  Google Scholar 

  111. Gurunathan, S. et al. Vaccination with DNA encoding the immunodominant LACK parasite antigen confers protective immunity to mice infected with Leishmania major. J. Exp. Med. 186, 1137–1147 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. Stober, C. B., Lange, U. G., Roberts, M. T., Alcami, A. & Blackwell, J. M. IL-10 from regulatory T cells determines vaccine efficacy in murine Leishmania major infection. J. Immunol. 175, 2517–2524 (2005). This study indicates that vaccination can also induce regulatory T cells that can interfere with the efficiency of the protective immune response.

    CAS  PubMed  Article  Google Scholar 

  113. Tabbara, K. S. et al. Conditions influencing the efficacy of vaccination with live organisms against Leishmania major infection. Infect. Immun. 73, 4714–4722 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Nardelli, D. T. et al. Association of CD4+ CD25+ T cells with prevention of severe destructive arthritis in Borrelia burgdorferi-vaccinated and challenged γ interferon-deficient mice treated with anti-interleukin-17 antibody. Clin. Diagn. Lab. Immunol. 11, 1075–1084 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Julia, V. et al. Priming by microbial antigens from the intestinal flora determines the ability of CD4+ T cells to rapidly secrete IL-4 in BALB/c mice infected with Leishmania major. J. Immunol. 165, 5637–5645 (2000).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  117. Singh, K. P., Gerard, H. C., Hudson, A. P., Reddy, T. R. & Boros, D. L. Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice. Immunology 114, 410–417 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. van der Kleij, D. et al. A novel host-parasite lipid cross-talk. Schistosomal lyso-phosphatidylserine activates Toll-like receptor 2 and affects immune polarization. J. Biol. Chem. 277, 48122–48129 (2002).

    CAS  PubMed  Article  Google Scholar 

  119. Braat, H. et al. Prevention of experimental colitis by parenteral administration of a pathogen-derived immunomodulatory molecule. Gut 56, 351–357 (2007).

    CAS  PubMed  Article  Google Scholar 

  120. Belkaid, Y., Blank, R. B. & Suffia, I. Natural regulatory T cells and parasites: a common quest for host homeostasis. Immunol. Rev. 212, 287–300 (2006).

    CAS  PubMed  Article  Google Scholar 

  121. Taylor, J. J., Mohrs, M. & Pearce, E. J. Regulatory T cell responses develop in parallel to Th responses and control the magnitude and phenotype of the Th effector population. J. Immunol. 176, 5839–5847 (2006).

    CAS  PubMed  Article  Google Scholar 

  122. Cai, X. P. et al. Dynamics of CD4+CD25+ T cells in spleens and mesenteric lymph nodes of mice infected with Schistosoma japonicum. Acta Biochim. Biophys. Sin (Shanghai) 38, 299–304 (2006).

    CAS  Article  Google Scholar 

  123. Campanelli, A. P. et al. CD4+CD25+ T cells in skin lesions of patients with cutaneous leishmaniasis exhibit phenotypic and functional characteristics of natural regulatory T cells. J. Infect. Dis. 193, 1313–1322 (2006).

    CAS  PubMed  Article  Google Scholar 

  124. Kitagaki, K. et al. Intestinal helminths protect in a murine model of asthma. J. Immunol. 177, 1628–1635 (2006).

    CAS  PubMed  Article  Google Scholar 

  125. Robertson, S. J., Messer, R. J., Carmody, A. B. & Hasenkrug, K. J. In vitro suppression of CD8+ T cell function by Friend virus-induced regulatory T cells. J. Immunol. 176, 3342–3349 (2006).

    CAS  PubMed  Article  Google Scholar 

  126. Zelinskyy, G., Kraft, A. R., Schimmer, S., Arndt, T. & Dittmer, U. Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection. Eur. J. Immunol. 36, 2658–2670 (2006).

    CAS  PubMed  Article  Google Scholar 

  127. Boettler, T. et al. T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J. Virol. 79, 7860–7867 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Li, S. et al. Defining target antigens for CD25+FOXP3+IFN-γ regulatory T cells in chronic hepatitis C virus infection. Immunol. Cell Biol. 85, 197–204 (2007).

    CAS  PubMed  Article  Google Scholar 

  129. Stoop, J. N., van der Molen, R. G., Kuipers, E. J., Kusters, J. G. & Janssen, H. L. Inhibition of viral replication reduces regulatory T cells and enhances the antiviral immune response in chronic hepatitis B. Virology 361, 141–148 (2007).

    CAS  PubMed  Article  Google Scholar 

  130. Yang, G. et al. Association of CD4+CD25+Foxp3+ regulatory T cells with chronic activity and viral clearance in patients with hepatitis B. Int. Immunol. 19, 133–140 (2007).

    CAS  PubMed  Article  Google Scholar 

  131. Yamano, Y. et al. Virus-induced dysfunction of CD4+CD25+ T cells in patients with HTLV-I-associated neuroimmunological disease. J. Clin. Invest. 115, 1361–1368 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Oh, U. et al. Reduced Foxp3 protein expression is associated with inflammatory disease during human T lymphotropic virus type 1 Infection. J. Infect. Dis. 193, 1557–1566 (2006).

    CAS  PubMed  Article  Google Scholar 

  133. Walsh, P. T. et al. A role for regulatory T cells in cutaneous T-Cell lymphoma; induction of a CD4+CD25+Foxp3+ T-cell phenotype associated with HTLV-1 infection. J. Invest. Dermatol. 126, 690–692 (2006).

    CAS  PubMed  Article  Google Scholar 

  134. 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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. Estes, J. D. et al. Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection. J. Infect. Dis. 193, 703–712 (2006).

    CAS  PubMed  Article  Google Scholar 

  136. Cavassani, K. A. et al. Systemic and local characterization of regulatory T cells in a chronic fungal infection in humans. J. Immunol. 177, 5811–5818 (2006).

    CAS  PubMed  Article  Google Scholar 

  137. Kaparakis, M. et al. CD4+ CD25+ regulatory T cells modulate the T-cell and antibody responses in helicobacter-infected BALB/c mice. Infect. Immun. 74, 3519–3529 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. McKinley, L. et al. Regulatory T cells dampen pulmonary inflammation and lung injury in an animal model of pneumocystis pneumonia. J. Immunol. 177, 6215–6226 (2006).

    CAS  PubMed  Article  Google Scholar 

  139. Quinn, K. M. et al. Inactivation of CD4+ CD25+ regulatory T cells during early mycobacterial infection increases cytokine production but does not affect pathogen load. Immunol. Cell Biol. 84, 467–474 (2006).

    CAS  PubMed  Article  Google Scholar 

  140. Chen, X. et al. CD4+CD25+FoxP3+ regulatory T cells suppress Mycobacterium tuberculosis immunity in patients with active disease. Clin. Immunol. 123, 50–59 (2007).

    CAS  PubMed  Article  Google Scholar 

  141. Faal, N. et al. Conjunctival FOXP3 expression in trachoma: do regulatory T cells have a role in human ocular Chlamydia trachomatis infection? PLoS Med. 3, e266 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. I apologize to those authors whose work I could not cite because of space limitations.

Author information

Authors and Affiliations

Authors

Related links

Related links

FURTHER INFORMATION

Yasmine Belkaid's homepage

Glossary

Colitis

An inflammatory disease of the colon. In humans, colitis is most commonly classified as ulcerative colitis or Crohn's disease, two inflammatory bowel diseases that have unknown aetiology. Various hereditary and induced mouse models of human colitis have been developed.

Filarial diseases

Diseases such as human river blindness and elephantiasis that are caused by filarial nematodes.

Thymic involution

The age-dependent decrease of thymic epithelial volume, which results in decreased production of T cells.

Bystander suppression

Inhibition of effector T-cell function by regulatory T cells of different antigen specificity.

Experimental autoimmune encephalomyelitis

(EAE). An experimental model of the human disease multiple sclerosis. EAE is an autoimmune disease mediated by CD4+ T helper 1 (TH1) cells and interleukin-17-producing TH17 cells reactive to components of the myelin sheath that infiltrate the nervous parenchyma, release pro-inflammatory cytokines and chemokines, promote leukocyte infiltration and contribute to demyelination.

Non-obese diabetic mice

(NOD mice). A strain of mice that normally develops idiopathic autoimmune diabetes that very closely resembles type 1 diabetes in humans. The target antigen(s) that is recognized by the pathogenic CD4+ T cells that initiate disease is expressed by pancreatic islet cells, but its identity has remained elusive.

Probiotic

Viable bacteria used therapeutically or prophylactically for colonization of the intestine for the purpose of modifying the intestinal microflora in ways presumed to be beneficial to the host.

B16 melanoma

A widely used experimental mouse melanoma. B16 melanoma is poorly immunogenic and therefore is difficult for the immune system to eliminate. Largely because of this, it makes a good model for testing cancer immunotherapies.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Belkaid, Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol 7, 875–888 (2007). https://doi.org/10.1038/nri2189

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2189

Further reading

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