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.
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.
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Sacks, D. & Sher, A. Evasion of innate immunity by parasitic protozoa. Nature Immunol. 3, 1041–1047 (2002).
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).
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).
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).
Shevach, E. M. et al. The lifestyle of naturally occurring CD4+CD25+Foxp3+ regulatory T cells. Immunol. Rev. 212, 60–73 (2006).
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).
Yamaguchi, T. et al. Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity 27, 145–159 (2007).
Tang, Q. et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nature Immunol. 7, 83–92 (2006).
von Boehmer, H. Mechanisms of suppression by suppressor T cells. Nature Immunol. 6, 338–344 (2005).
Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nature Immunol. 4, 1206–1212 (2003).
Bopp, T. et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J. Exp. Med. 204, 1303–1310 (2007).
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).
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).
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).
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.
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.
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).
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.
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.
Rouse, B. T., Sarangi, P. P. & Suvas, S. Regulatory T cells in virus infections. Immunol. Rev. 212, 272–286 (2006).
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).
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).
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).
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).
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).
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).
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).
Cabrera, R. et al. An immunomodulatory role for CD4+CD25+ regulatory T lymphocytes in hepatitis C virus infection. Hepatology 40, 1062–1071 (2004).
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).
Boyer, O. et al. CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. Blood 103, 3428–3430 (2004).
Hsieh, C. S. et al. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21, 267–277 (2004).
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).
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).
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.
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).
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.
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).
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).
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).
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).
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).
Plebanski, M. et al. Interleukin 10-mediated immunosuppression by a variant CD4 T cell epitope of Plasmodium falciparum. Immunity 10, 651–660 (1999).
Boussiotis, V. A. et al. IL-10-producing T cells suppress immune responses in anergic tuberculosis patients. J. Clin. Invest. 105, 1317–1325 (2000).
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).
Carvalho, E. M. et al. Restoration of IFN-γ production and lymphocyte proliferation in visceral leishmaniasis. J. Immunol. 152, 5949–5956 (1994).
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).
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.
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).
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).
Roncarolo, M. G. et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212, 28–50 (2006).
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).
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.
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).
Marshall, N. A. et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 103, 1755–1762 (2004).
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).
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).
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).
Trinchieri, G. Regulatory role of T cells producing both interferon γ and interleukin 10 in persistent infection. J. Exp. Med. 194, F53–F57 (2001).
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).
Anderson, C. F., Oukka, M., Kuchroo, V. J. & Sacks, D. CD4+CD25−Foxp3− 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.
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).
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).
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).
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).
Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).
Kretschmer, K. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nature Immunol. 6, 1219–1227 (2005).
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).
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).
Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329–341 (2005).
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).
Montagnoli, C. et al. Immunity and tolerance to Aspergillus involve functionally distinct regulatory T cells and tryptophan catabolism. J. Immunol. 176, 1712–1723 (2006).
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).
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).
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).
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).
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).
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.
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).
Maizels, R. M. Infections and allergy — helminths, hygiene and host immune regulation. Curr. Opin. Immunol. 17, 656–661 (2005).
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.
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).
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).
Singer, S. M. & Nash, T. E. The role of normal flora in Giardia lamblia infections in mice. J. Infect. Dis. 181, 1510–1512 (2000).
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).
Sutmuller, R. P. et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J. Clin. Invest. 116, 485–494 (2006).
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).
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).
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).
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).
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).
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).
Grant, C. et al. Foxp3 represses retroviral transcription by targeting both NF-κB and CREB pathways. PLoS Pathog. 2, e33 (2006).
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).
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).
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).
Sebastiani, S. et al. Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity. J. Immunol. 166, 996–1002 (2001).
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).
Belkaid, Y. & Rouse, B. T. Natural regulatory T cells in infectious disease. Nature Immunol. 6, 353–360 (2005).
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).
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).
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).
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).
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).
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).
Kursar, M. et al. Regulatory CD4+CD25+ T cells restrict memory CD8+ T cell responses. J. Exp. Med. 196, 1585–1592 (2002).
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.
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).
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).
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.
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).
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).
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.
Tabbara, K. S. et al. Conditions influencing the efficacy of vaccination with live organisms against Leishmania major infection. Infect. Immun. 73, 4714–4722 (2005).
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).
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).
Mottet, C., Uhlig, H. H. & Powrie, F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J. Immunol. 170, 3939–3943 (2003).
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).
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).
Braat, H. et al. Prevention of experimental colitis by parenteral administration of a pathogen-derived immunomodulatory molecule. Gut 56, 351–357 (2007).
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).
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).
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).
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).
Kitagaki, K. et al. Intestinal helminths protect in a murine model of asthma. J. Immunol. 177, 1628–1635 (2006).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
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.
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.
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Belkaid, Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol 7, 875–888 (2007). https://doi.org/10.1038/nri2189
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