Key Points
-
There are distinct populations of natural and inducible regulatory T cells that have the common property of suppressing immune responses. Natural regulatory T cells arise in the thymus and express CD25 and the transcriptional repressor FOXP3 (forkhead box P3), whereas inducible regulatory T cells are generated from naive T cells in the periphery after encounter with antigen.
-
Regulatory T cells suppress the proliferation of and cytokine production by T helper 1 (TH1) cells, TH2 cells and CD8+ T cells, either by cell–cell contact mechanisms or through production of the immunosuppressive cytokines interleukin-10 (IL-10) and transforming growth factor-β.
-
Infection with many (and perhaps all) pathogens that cause persistent or chronic infections is associated with the induction of regulatory T cells specific for pathogen-derived antigens.
-
The induction of regulatory T cells specific for pathogen-derived antigens is directed by semi-mature dendritic cells, which have an intermediate phenotype that includes low-level expression of CD40 and production of IL-12 but high levels of IL-10 production.
-
Immune responses that help to eliminate pathogens can cause collateral damage to host tissues, and if they are not tightly regulated, they can exacerbate the course of disease through the development of immunopathology. Regulatory T cells have a protective role in infection by limiting pathogen-induced immunopathology, while allowing the development of immunological memory.
-
Most pathogens have evolved sophisticated mechanisms of survival through the evasion and subversion of host immune responses. Regulatory T cells can be exploited by pathogens to subvert the protective immune responses of the host, thereby enabling pathogen persistence and the development of a state of chronic infection.
-
Suppression of the activation of regulatory T cells or their cytokine production is a promising approach for the development of therapies for chronic infections, as well as cancer, but it has the risk of promoting inflammation and autoimmunity.
Abstract
Homeostasis in the immune system depends on a balance between the responses that control infection and tumour growth and the reciprocal responses that prevent inflammation and autoimmune diseases. It is now recognized that regulatory T cells have a crucial role in suppressing immune responses to self-antigens and in preventing autoimmune diseases. Evidence is also emerging that regulatory T cells control immune responses to bacteria, viruses, parasites and fungi. This article explores the possibility that regulatory T cells can be both beneficial to the host, through limiting the immunopathology associated with anti-pathogen immune responses, and beneficial to the pathogen, through subversion of the protective immune responses of the host.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Artavanis-Tsakonas, K., Tongren, J. E. & Riley, E. M. The war between the malaria parasite and the immune system: immunity, immunoregulation and immunopathology. Clin. Exp. Immunol. 133, 145–152 (2003).
von Herrath, M. G. & Harrison, L. C. Antigen-induced regulatory T cells in autoimmunity. Nature Rev. Immunol. 3, 223–232 (2003).
Redpath, S., Ghazal, P. & Gascoigne, N. R. Hijacking and exploitation of IL-10 by intracellular pathogens. Trends Microbiol. 9, 86–92 (2001).
Reed, S. G. TGF-β in infections and infectious diseases. Microbes Infect. 1, 1313–1325 (1999).
Yazdanbakhsh, M., Kremsner, P. G. & van Ree, R. Allergy, parasites, and the hygiene hypothesis. Science 296, 490–494 (2002).
Braun-Fahrlander, C. et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N. Engl. J. Med. 347, 869–877 (2002).
Mills, K. H. G. & Boyd, A. in Topley and Wilsons's Microbiology and Microbial Infections 10th edn (eds Kaufmann, S. H. & Steward, M.) (Edward Arnold Publishers Ltd, London, in press).
McGuirk, P. & Mills, K. H. G. Pathogen-specific regulatory T cells provoke a shift in the TH1/TH2 paradigm in immunity to infectious diseases. Trends Immunol. 23, 450–455 (2002).
Cozzo, C., Larkin, J. & Caton, A. J. Self-peptides drive the peripheral expansion of CD4+CD25+ regulatory T cells. J. Immunol. 171, 5678–5682 (2003).
Bluestone, J. A. & Abbas, A. K. Natural versus adaptive regulatory T cells. Nature Rev. Immunol. 3, 253–257 (2003).
Garba, M. L., Pilcher, C. D., Bingham, A. L., Eron, J. & Frelinger, J. A. HIV antigens can induce TGF-β1-producing immunoregulatory CD8+ T cells. J. Immunol. 168, 2247–2254 (2002).
Haynes, L. M., Vanderlugt, C. L., Dal Canto, M. C., Melvold, R. W. & Miller, S. D. CD8+ T cells from Theiler's virus-resistant BALB/cByJ mice downregulate pathogenic virus-specific CD4+ T cells. J. Neuroimmunol. 106, 43–52 (2000).
Harrison, L. C., Dempsey-Collier, M., Kramer, D. R. & Takahashi, K. Aerosol insulin induces regulatory CD8 γδ T cells that prevent murine insulin-dependent diabetes. J. Exp. Med. 184, 2167–2174 (1996).
Seo, N., Tokura, Y., Takigawa, M. & Egawa, K. Depletion of IL-10- and TGF-β-producing regulatory γδ T cells by administering a daunomycin-conjugated specific monoclonal antibody in early tumor lesions augments the activity of CTLs and NK cells. J. Immunol. 163, 242–249 (1999).
Sonoda, K. H. et al. NK T cell-derived IL-10 is essential for the differentiation of antigen-specific T regulatory cells in systemic tolerance. J. Immunol. 166, 42–50 (2001).
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). The first description of CD25 as a marker for T Reg cells and the demonstration that these cells can suppress immune responses that mediate autoimmune diseases.
Powrie, F., Carlino, J., Leach, M. W., Mauze, S. & Coffman, R. L. A critical role for transforming growth factor-β but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RBlowCD4+ T cells. J. Exp. Med. 183, 2669–2674 (1996).
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).
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).
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).
Richman, L. K., Chiller, J. M., Brown, W. R., Hanson, D. G. & Vaz, N. M. Enterically induced immunologic tolerance. I. Induction of suppressor T lymphocytes by intragastric administration of soluble proteins. J. Immunol. 121, 2429–2434 (1978).
Miller, A., Lider, O., Roberts, A. B., Sporn, M. B. & Weiner, H. L. Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor-β after antigen-specific triggering. Proc. Natl Acad. Sci. USA 89, 421–425 (1992).
Hirai, K. et al. Suppression of cell-mediated immunity by street rabies virus infection. Microbiol. Immunol. 36, 1277–1290 (1992).
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).
Boussiotis, V. A. et al. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J. Clin. Invest. 105, 1317–1325 (2000).
Chen, Y., Kuchroo, V. K., Inobe, J., Hafler, D. A. & Weiner, H. L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240 (1994).
Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997). The first description of T R 1-cell clones and their ability to prevent inflammatory disease.
McGuirk, P., McCann, C. & Mills, K. H. G. 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). The first demonstration of T R 1 cells specific for a bacterial antigen, their cloning from a mucosal site of infection and a role for IL-10 produced by DCs in their induction.
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). The first description of a role for CD4+CD25+ TReg cells in protective immunity to infection and in the development of immunological memory to a parasite.
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).
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).
Lavelle, E. C. et al. Cholera toxin promotes the induction of regulatory T cells specific for bystander antigens by modulating dendritic cell activation. J. Immunol. 171, 2384–2392 (2003).
Cottrez, F., Hurst, S. D., Coffman, R. L. & Groux, H. T regulatory cells 1 inhibit a TH2-specific response in vivo. J. Immunol. 165, 4848–4853 (2000).
Piccirillo, C. A. & Shevach, E. M. Control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J. Immunol. 167, 1137–1140 (2001).
Kursar, M. et al. Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses. J. Exp. Med. 196, 1585–1592 (2002).
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).
Maloy, K. J. et al. CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003). This paper describes the role of CD45RBhi T Reg cells in the prevention of bacteria-induced inflammation in the intestine.
Kitani, A., Chua, K., Nakamura, K. & Strober, W. Activated self-MHC-reactive T cells have the cytokine phenotype of TH3/T regulatory cell 1 T cells. J. Immunol. 165, 691–702 (2000).
Gorelik, L., Constant, S. & Flavell, R. A. Mechanism of transforming growth factor β-induced inhibition of T helper type 1 differentiation. J. Exp. Med. 195, 1499–1505 (2002).
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).
Kitani, A. et al. Transforming growth factor (TGF)-β1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-β1-mediated fibrosis. J. Exp. Med. 198, 1179–1188 (2003).
Grundstrom, S., Cederbom, L., Sundstedt, A., Scheipers, P. & Ivars, F. Superantigen-induced regulatory T cells display different suppressive functions in the presence or absence of natural CD4+CD25+ regulatory T cells in vivo. J. Immunol. 170, 5008–5017 (2003).
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).
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).
Barthlott, T., Kassiotis, G. & Stockinger, B. T cell regulation as a side effect of homeostasis and competition. J. Exp. Med. 197, 451–460 (2003).
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).
Doetze, A. et al. Antigen-specific cellular hyporesponsiveness in a chronic human helminth infection is mediated by TH3/TR1-type cytokines IL-10 and transforming growth factor-β but not by a TH1 to TH2 shift. Int. Immunol. 12, 623–630 (2000). The first demonstration of parasite-specific T R 1 and T H 3 cells at the clonal level in humans.
Satoguina, J. et al. Antigen-specific T regulatory-1 cells are associated with immunosuppression in a chronic helminth infection (onchocerciasis). Microbes Infect. 4, 1291–1300 (2002).
Accapezzato, D. et al. Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection. J. Clin. Invest. 113, 963–972 (2004).
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).
Delgado, J. C. et al. Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia. Proc. Natl Acad. Sci. USA 99, 7576–7581 (2002).
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).
Ostrowski, M. A. et al. Quantitative and qualitative assessment of human immunodeficiency virus type 1 (HIV-1)-specific CD4+ T cell immunity to gag in HIV-1-infected individuals with differential disease progression: reciprocal interferon-γ and interleukin-10 responses. J. Infect. Dis. 184, 1268–1278 (2001).
Beilharz, M. W. et al. Timed ablation of regulatory CD4+ T cells can prevent murine AIDS progression. J. Immunol. 172, 4917–4925 (2004).
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).
Kullberg, M. C. et al. Bacteria-triggered CD4+ T regulatory cells suppress Helicobacter hepaticus-induced colitis. J. Exp. Med. 196, 505–515 (2002).
Graca, L., Le Moine, A., Cobbold, S. P. & Waldmann, H. Dominant transplantation tolerance. Curr. Opin. Immunol. 15, 499–506 (2003).
Chen, C., Lee, W. H., Yun, P., Snow, P. & Liu, C. P. Induction of autoantigen-specific TH2 and TR1 regulatory T cells and modulation of autoimmune diabetes. J. Immunol. 171, 733–744 (2003).
Akdis, M. et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J. Exp. Med. 199, 1567–1575 (2004).
Brady, M. T., MacDonald, A. J., Rowan, A. G. & Mills, K. H. Hepatitis C virus non-structural protein 4 suppresses TH1 responses by stimulating IL-10 production from monocytes. Eur. J. Immunol. 33, 3448–3457 (2003).
Boyer, O. et al. CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. Blood 103, 3428–3430 (2004).
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). This study shows that CD25+ T Reg cells suppress CD4+ T-cell responses in vivo and limit inflammation during corneal infection with HSV.
Deckert, M. et al. Endogenous interleukin-10 is required for prevention of a hyperinflammatory intracerebral immune response in Listeria monocytogenes meningoencephalitis. Infect. Immun. 69, 4561–4571 (2001).
Sewnath, M. E. et al. IL-10-deficient mice demonstrate multiple organ failure and increased mortality during Escherichia coli peritonitis despite an accelerated bacterial clearance. J. Immunol. 166, 6323–6331 (2001).
Chen, W., Shu, D. & Chadwick, V. S. Helicobacter pylori infection: mechanism of colonization and functional dyspepsia. Reduced colonization of gastric mucosa by Helicobacter pylori in mice deficient in interleukin-10. J. Gastroenterol. Hepatol. 16, 377–383 (2001).
Kullberg, M. C. et al. Helicobacter hepaticus-induced colitis in interleukin-10-deficient mice: cytokine requirements for the induction and maintenance of intestinal inflammation. Infect. Immun. 69, 4232–4241 (2001).
Higgins, S. C. et al. Toll-like receptor 4-mediated innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by inhibiting inflammatory pathology. J. Immunol. 171, 3119–3127 (2003). This paper describes a role for TLR4 in the induction of IL-10 production by innate immune cells and regulatory T cells and its role in preventing bacteria-induced lung inflammation.
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).
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). This paper shows that regulatory T cells can increase the pathogen load but protect the host by limiting lung inflammation and the wasting syndrome induced by P. carinii.
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).
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).
May, J., Lell, B., Luty, A. J., Meyer, C. G. & Kremsner, P. G. Plasma interleukin-10: tumor necrosis factor (TNF)-α ratio is associated with TNF promoter variants and predicts malarial complications. J. Infect. Dis. 182, 1570–1573 (2000).
Othoro, C. et al. A low interleukin-10 tumor necrosis factor-α ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya. J. Infect. Dis. 179, 279–282 (1999).
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).
Omer, F. M. & Riley, E. M. Transforming growth factor-β production is inversely correlated with severity of murine malaria infection. J. Exp. Med. 188, 39–48 (1998).
Omer, F. M., de Souza, J. B. & Riley, E. M. Differential induction of TGF-β regulates proinflammatory cytokine production and determines the outcome of lethal and nonlethal Plasmodium yoelii infections. J. Immunol. 171, 5430–5436 (2003).
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).
Xu, D. et al. 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).
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).
Clerici, M. & Shearer, G. M. The TH1–TH2 hypothesis of HIV infection: new insights. Immunol. Today 15, 575–581 (1994).
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).
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).
Iwashiro, M. et al. Immunosuppression by CD4+ regulatory T cells induced by chronic retroviral infection. Proc. Natl Acad. Sci. USA 98, 9226–9230 (2001).
Dittmer, U. et al. Functional impairment of CD8+ T cells by regulatory T cells during persistent retroviral infection. Immunity 20, 293–303 (2004). This study describes a role for IL-10-secreting CD4+ regulatory T cells in suppressing the protective effect of CD8+ CTLs in a viral infection.
Turner, J. et al. In vivo IL-10 production reactivates chronic pulmonary tuberculosis in C57BL/6 mice. J. Immunol. 169, 6343–6351 (2002).
Jacobs, M., Brown, N., Allie, N., Gulert, R. & Ryffel, B. Increased resistance to mycobacterial infection in the absence of interleukin-10. Immunology 100, 494–501 (2000).
Sing, A., Roggenkamp, A., Geiger, A. M. & Heesemann, J. Yersinia enterocolitica evasion of the host innate immune response by V antigen-induced IL-10 production of macrophages is abrogated in IL-10-deficient mice. J. Immunol. 168, 1315–1321 (2002).
Ross, P. J., Lavelle, E. C., Mills, K. H. G. & Boyd, A. P. Adenylate cyclase toxin from Bordetella pertussis synergises with lipopolysaccaride to promote innate IL-10 production and enhance the induction of TH2 and regulatory T cells. Infect. Immun. 72, 1568–1579 (2003).
McGuirk, P., Mahon, B. P., Griffin, F. & Mills, K. H. G. Compartmentalization of T cell responses following respiratory infection with Bordetella pertussis: hyporesponsiveness of lung T cells is associated with modulated expression of the co-stimulatory molecule CD28. Eur. J. Immunol. 28, 153–163 (1998).
Kursar, M., Kohler, A., Kaufmann, S. H. & Mittrucker, H. W. Depletion of CD4+ T cells during immunization with nonviable Listeria monocytogenes causes enhanced CD8+ T cell-mediated protection against listeriosis. J. Immunol. 172, 3167–3172 (2004).
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 shows that depletion of natural regulatory T cells allows the host immune response to clear a parasite infection.
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).
Noben-Trauth, N., Lira, R., Nagase, H., Paul, W. E. & Sacks, D. L. The relative contribution of IL-4 receptor signaling and IL-10 to susceptibility to Leishmania major. J. Immunol. 170, 5152–5158 (2003).
Sacks, D. & Noben-Trauth, N. The immunology of susceptibility and resistance to Leishmania major in mice. Nature Rev. Immunol. 2, 845–858 (2002).
Jonuleit, H., Schmitt, E., Schuler, G., Knop, J. & Enk, A. H. Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med. 192, 1213–1222 (2000).
Martin, E., O'Sullivan, B., Low, P. & Thomas, R. Antigen-specific suppression of a primed immune response by dendritic cells mediated by regulatory T cells secreting interleukin-10. Immunity 18, 155–167 (2003).
von der Weid, T., Bulliard, C. & Schiffrin, E. J. Induction by a lactic acid bacterium of a population of CD4+ T cells with low proliferative capacity that produce transforming growth factor-β and interleukin-10. Clin. Diagn. Lab. Immunol. 8, 695–701 (2001).
Caramalho, I. et al. Regulatory T cells selectively express Toll-like receptors and are activated by lipopolysaccharide. J. Exp. Med. 197, 403–411 (2003).
Kemper, C. et al. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421, 388–392 (2003).
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).
Bynoe, M. S., Evans, J. T., Viret, C. & Janeway, C. A. Jr. Epicutaneous immunization with autoantigenic peptides induces T suppressor cells that prevent experimental allergic encephalomyelitis. Immunity 19, 317–328 (2003).
Golgher, D., Jones, E., Powrie, F., Elliott, T. & Gallimore, A. Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens. Eur. J. Immunol. 32, 3267–3275 (2002).
Acknowledgements
I acknowledge support from Science Foundation Ireland, The Irish Health Research Board and Enterprise Ireland, and I am grateful to P. McGuirk and E. Lavelle for helpful discussions.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
Kingston H. G. Mills is a founder, director and shareholder of a University Campus Company, Opsona Therapeuticas Ltd, which was established to exploit intellectual property arising from research in his laboratory, and that of two colleagues, at Trinity College Dublin, Ireland.
Related links
Related links
DATABASES
Entrez Gene
Infectious Disease Information
Glossary
- CHRONIC INFECTIONS
-
Infections that persist for a long time, often indefinitely, and might not be cleared following the development of anti-pathogen immune responses. These include infection with HIV, hepatitis C virus and many parasites.
- PERSISTENT INFECTIONS
-
Non-lethal infections (such as infection with Bordetella pertussis) that are not cleared immediately (lasting for weeks or months rather than days) and are usually associated with the delayed development or suppression of anti-pathogen immune responses. In persistent viral infections, virus production occurs in a cell that is not killed by the virus (non-lytic); this includes chronic, latent and transforming infections.
- ANTIGENIC VARIATION
-
Changes in the composition, structure or amino-acid sequence of antigenic components of pathogens recognized by T or B cells, which allow the microorganism to escape recognition by the adaptive immune response.
- ATHYMIC
-
Mice that lack a thymus and are therefore deficient in T cells.
- NUDE
-
A mutation in mice that causes both hairlessness and defective formation of the thymus, which results in a lack of mature T cells.
- ANERGIC
-
A state of unresponsiveness by T or B cells to antigens. After stimulation, anergic T cells cannot produce interleukin-2 or proliferate, even in the presence of co-stimulatory signals.
- MIXED CRYOGLOBULINAEMIA
-
Cryoglobulins are antibodies that precipitate at cold temperatures and dissolve on warming. Mixed cryoglobulinaemia is a B-cell proliferative disorder that is characterized by polyclonal B-cell activation and autoantibody production. Patients with mixed cryoglobulinaemia have circulating cryoproteins and inflammation of small blood vessels, with inflammatory changes prominent in the skin (vasculitis), and might have renal and neurological involvement.
- DEMYELINATING
-
Causing damage to the myelin sheath surrounding nerves in the brain and spinal cord, which affects the function of the nerves involved. Demyelination occurs in multiple sclerosis, a chronic disease of the nervous system affecting young and middle-aged adults, and in experimental autoimmune encephalomyelitis, which is a mouse model of multiple sclerosis.
- SECONDARY INFECTION
-
An infection in a host already infected with another pathogen, often caused by opportunistic pathogens in immunodeficient or immunosuppressed hosts.
- TOLL-LIKE RECEPTOR
-
(TLR). A member of a family of receptors that recognize pathogen-associated molecular patterns. TLRs recognize conserved molecular patterns that are common to large groups of microorganisms and/or viruses.
- SEVERE COMBINED IMMUNODEFICIENT
-
(SCID). Mice with this immune-system defect do not have B or T cells and therefore can accept tumour cells from another species without rejection.
- ALLOREACTIVE
-
Responding to antigens that are distinct between members of the same species, such as MHC molecules or blood-group antigens.
Rights and permissions
About this article
Cite this article
Mills, K. Regulatory T cells: friend or foe in immunity to infection?. Nat Rev Immunol 4, 841–855 (2004). https://doi.org/10.1038/nri1485
Issue Date:
DOI: https://doi.org/10.1038/nri1485
This article is cited by
-
Standardized astragalus extract for attenuation of the immunosuppression induced by strenuous physical exercise: randomized controlled trial
Journal of the International Society of Sports Nutrition (2021)
-
The immune response of young turkeys to haemorrhagic enteritis virus infection at different levels and sources of methionine in the diet
BMC Veterinary Research (2019)
-
An attempt to induce an immunomodulatory effect in rowers with spirulina extract
Journal of the International Society of Sports Nutrition (2018)
-
Regulatory T cell-derived extracellular vesicles modify dendritic cell function
Scientific Reports (2018)
-
Anti-inflammatory effects of heat-killed Lactobacillus plantarum L-137 on cardiac and adipose tissue in rats with metabolic syndrome
Scientific Reports (2018)