The Role of IL-10 and TGF-β in the Differentiation and Effector Function of T Regulatory CellsLevings M.K.a · Bacchetta R.a · Schulz U.a · Roncarolo M.G.a,b
aSan Raffaele Telethon Institute for Gene Therapy, and bUniversità Vita-Salute San Raffaele, Milan, Italy
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Suppression by T regulatory (Tr) cells is essential for the induction of peripheral tolerance. Many types of CD4+ Tr cells have been described in a number of systems, and although the precise mechanisms which mediate their effects remain to be defined, it is well established that they can suppress immune responses via cell-cell interactions and/or the production of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β). Type 1 T regulatory (Tr1) cells are defined by their ability to produce high levels of IL-10 and TGF-β, and these cytokines mediate their ability to suppress pathological immune responses in the settings of transplantation, allergy and autoimmune disease. Tr1 cell activity is not necessarily beneficial, and they can also suppress immune responses to antigens from tumours and pathogens. In vivo, the differentiation of Tr1 cells is likely controlled by certain dendritic cells which promote IL-10 production and may express tolerogenic costimulatory molecules. Another subset of CD4+ Tr cells is defined by constitutive expression of CD25, and although these CD4+CD25+ Tr cells appear to suppress via mechanisms which are largely independent of cytokines, they may actively promote the differentiation of Tr1 cells. Many questions about the basic biology of Tr1 cells remain to be answered, but the development of therapeutic strategies designed to harness their immunoregulatory effects can already be contemplated.
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- Gershon RK, Kondo K: Infectious immunological tolerance. Immunology 1971;21:903–914.
- Roncarolo MG, Levings MK: The role of different subsets of T regulatory cells in controlling autoimmunity. Curr Opin Immunol 2000;12:676–683.
- Parham P: Regulatory T Cells. Immunol Rev 2001;182:5–227.
- Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A: Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683–765.
- Fickenscher H, Hor S, Kupers H, Knappe A, Wittmann S, Sticht H: The interleukin-10 family of cytokines. Trends Immunol 2002;23:89–96.
- Liu Y, Wei SH, Ho AS, de Waal Malefyt R, Moore KW: Expression cloning and characterization of a human IL-10 receptor. J Immunol 1994;152:1821–1829.
- MacDonald KP, Pettit AR, Quinn C, Thomas GJ, Thomas R: Resistance of rheumatoid synovial dendritic cells to the immunosuppressive effects of IL-10. J Immunol 1999;163:5599–5607.
- Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kuhn R, Muller W, Trinchieri G, Sher A: 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-gamma and TNF-alpha. J Immunol 1996;157:798–805.
- Letterio JJ, Roberts AB: Regulation of immune responses by TGF-beta. Annu Rev Immunol 1998;16:137–161.
- Attisano L, Wrana JL: Signal transduction by the TGF-beta superfamily. Science 2002;296:1646–1647.
Gleizes PE, Munger JS, Nunes I, Harpel JG, Mazzieri R, Noguera I, Rifkin DB: TGF-beta latency: Biological significance and mechanisms of activation. Stem Cells 1997;15:190–197.
- Gorelik L, Flavell RA: Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2002;2:46–53.
- Gorelik L, Constant S, Flavell RA: Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 2002;195:1499–1505.
- Heath VL, Murphy EE, Crain C, Tomlinson MG, O’Garra A: TGF-beta1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression. Eur J Immunol 2000;30:2639–2649.
- De Winter H, Elewaut D, Turovskaya O, Huflejt M, Shimeld C, Hagenbaugh A, Binder S, Takahashi I, Kronenberg M, Cheroutre H: Regulation of mucosal immune responses by recombinant interleukin 10 produced by intestinal epithelial cells in mice. Gastroenterology 2002;122:1829–1841.
- Seder RA, Marth T, Sieve MC, Strober W, Letterio JJ, Roberts AB, Kelsall B: Factors involved in the differentiation of TGF-beta-producing cells from naive CD4+ T cells: IL-4 and IFN-gamma have opposing effects, while TGF-beta positively regulates its own production. J Immunol 1998;160:5719–5728.
- Fuss IJ, Boirivant M, Lacy B, Strober W: The interrelated roles of TGF-beta and IL-10 in the regulation of experimental colitis. J Immunol 2002;168:900–908.
- Cottrez F, Groux H: Regulation of TGF-beta response during T cell activation is modulated by IL-10. J Immunol 2001;167:773–778.
- Kitani A, Fuss IJ, Nakamura K, Schwartz OM, Usui T, Strober W: Treatment of experimental (trinitrobenzene sulfonic acid) colitis by intranasal administration of transforming growth factor (TGF)-beta1 plasmid: TGF-beta1-mediated suppression of T helper cell type 1 response occurs by interleukin (IL)-10 induction and IL-12 receptor beta2 chain downregulation. J Exp Med 2000;192:41–52.
- Blokzijl A, ten Dijke P, Ibanez CF: Physical and functional interaction between GATA-3 and Smad3 allows TGF-beta regulation of GATA target genes. Curr Biol 2002;12:35–45.
- Jenkins MK, Chen CA, Jung G, Mueller DL, Schwartz RH: Inhibition of antigen-specific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3 monoclonal antibody. J Immunol 1990;144:16–22.
- Groux H, Bigler M, de Vries JE, Roncarolo MG: Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med 1996;184:19–29.
- Steinbrink K, Graulich E, Kubsch S, Knop J, Enk AH: CD4(+) and CD8(+) anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood 2002;99:2468–2476.
- Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG: A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737–742.
- Roncarolo MG, Levings MK, Traversari C: Differentiation of T regulatory cells by immature dendritic cells. J Exp Med 2001;193:F5–9.
- Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK: Type 1 T regulatory cells. Immunol Rev 2001;182:68–79.
- Ludviksson BR, Seegers D, Resnick AS, Strober W: The effect of TGF-beta1 on immune responses of naive versus memory CD4+ Th1/Th2 T cells. Eur J Immunol 2000;30:2101–2111.
- Zeller JC, Panoskaltsis-Mortari A, Murphy WJ, Ruscetti FW, Narula S, Roncarolo MG, Blazar BR: Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-beta. J Immunol 1999;163:3684–3691.
- Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt R, Roncarolo MG: IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 2001;166:5530–5539.
- Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA: A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol 2001;166:7282–7289.
- Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF, de Waal-Malefyt R, Coffman RL, Hawrylowicz CM, O’Garra A: In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 2002;195:603–616.
- Bacchetta R, Sartirana C, Levings MK, Bordignon C, Narula S, Roncarolo MG: Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines. Eur J Immunol 2002;32:2237–2245.
- Sebastiani S, Allavena P, Albanesi C, Nasorri F, Bianchi G, Traidl C, Sozzani S, Girolomoni G, Cavani A: Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity. J Immunol 2001;166:996–1002.
- Lecart S, Boulay V, Raison-Peyron N, Bousquet J, Meunier L, Yssel H, Pene J: Phenotypic characterization of human CD4+ regulatory T cells obtained from cutaneous dinitrochlorobenzene-induced delayed type hypersensitivity reactions. J Invest Dermatol 2001;117:318–325.
- Cavani A, Nasorri F, Prezzi C, Sebastiani S, Albanesi C, Girolomoni G: Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses. J Invest Dermatol 2000;114:295–302.
- 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 2000;165:691–702.
- Graca L, Cobbold SP, Waldmann H: Identification of regulatory T cells in tolerated allografts. J Exp Med 2002;195:1641–1646.
- Iwashiro M, Messer RJ, Peterson KE, Stromnes IM, Sugie T, Hasenkrug KJ: Immunosuppression by CD4+ regulatory T cells induced by chronic retroviral infection. Proc Natl Acad Sci USA 2001;98:9226–9230.
Mahnke K, Schmitt E, Bonifaz L, Enk AH, Jonuleit H: Immature, but not inactive: The tolerogenic function of immature dendritic cells. Immunol Cell Biol 2002;80:477–483.
- Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH: Induction of interleukin-10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogenic immature human dendritic cells. J Exp Med 2000;192:1213–1222.
- Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N: Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 2001;193:233–238.
- Penna G, Adorini L: 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 2000;164:2405–2411.
- McGuirk P, McCann C, Mills KH: 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 2002;195:221–231.
- Gray CP, Arosio P, Hersey P: Heavy chain ferritin activates regulatory T cells by induction of changes in dendritic cells. Blood 2002;99:3326–3334.
- Hackstein H, Morelli AE, Thomson AW: Designer dendritic cells for tolerance induction: Guided not misguided missiles. Trends Immunol 2001;22:437–442.
- Greenwald RJ, Latchman YE, Sharpe AH: Negative co-receptors on lymphocytes. Curr Opin Immunol 2002;14:391–396.
- Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, Berry G, DeKruyff RH, Umetsu DT: Antigen-specific regulatory T cells develop via the ICOS#150; ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 2002;8:1024–1032.
- Wakkach A, Cottrez F, Groux H: Differentiation of regulatory T cells 1 is induced by CD2 costimulation. J Immunol 2001;167:3107–3113.
- Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS, Keskin DB, Marshall B, Chandler P, Antonia SJ, Burgess R, Slingluff CL Jr, Mellor AL: Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 2002;297:1867–1870.
- Lu L, Bonham CA, Liang X, Chen Z, Li W, Wang L, Watkins SC, Nalesnik MA, Schlissel MS, Demestris AJ, Fung JJ, Qian S: Liver-derived DEC205+B220+CD19– dendritic cells regulate T cell responses. J Immunol 2001;166:7042–7052.
- Akbari O, DeKruyff RH, Umetsu DT: Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2001;2:725–731.
- Iwasaki A, Kelsall BL: Freshly isolated Peyer’s patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells. J Exp Med 1999;190:229–239.
- Asselin-Paturel C, Boonstra A, Dalod M, Durand I, Yessaad N, Dezutter-Dambuyant C, Vicari A, O’Garra A, Biron C, Briere F, Trinchieri G: Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat Immunol 2001;2:1144–1150.
- Gilliet M, Liu YJ: Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J Exp Med 2002;195:695–704.
- Kadowaki N, Antonenko S, Lau JY, Liu YJ: Natural interferon alpha/beta-producing cells link innate and adaptive immunity. J Exp Med 2000;192:219–226.
- Arpinati M, Green CL, Heimfeld S, Heuser JE, Anasetti C: Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. Blood 2000;95:2484–2490.
- Rutella S, Pierelli L, Bonanno G, Sica S, Ameglio F, Capoluongo E, Mariotti A, Scambia G, D’Onofrio G, Leone G: Role for granulocyte colony-stimulating factor in the generation of human T regulatory type 1 cells. Blood 2002;100:2562–2571.
- Waldmann H, Cobbold S: Regulating the immune response to transplants. A role for CD4+ regulatory cells? Immunity 2001;14:399–406.
- Bacchetta R, Bigler M, Touraine JL, Parkman R, Tovo PA, Abrams J, de Waal Malefyt R, de Vries JE, Roncarolo MG: High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med 1994;179:493–502.
- Holler E, Roncarolo MG, Hintermeier-Knabe R, Eissner G, Ertl B, Schulz U, Knabe H, Kolb HJ, Andreesen R, Wilmanns W: Prognostic significance of increased IL-10 production in patients prior to allogeneic bone marrow transplantation. Bone Marrow Transplant 2000;25:237–241.
- VanBuskirk AM, Burlingham WJ, Jankowska-Gan E, Chin T, Kusaka S, Geissler F, Pelletier RP, Orosz CG: Human allograft acceptance is associated with immune regulation. J Clin Invest 2000;106:145–155.
- Yudoh K, Matsuno H, Nakazawa F, Yonezawa T, Kimura T: Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis. Arthritis Rheum 2000;43:617–627.
- Wildbaum G, Netzer N, Karin N: Tr1 cell-dependent active tolerance blunts the pathogenic effects of determinant spreading. J Clin Invest 2002;110:701–710.
- McGuirk P, Mills K: Pathogen-specific regulatory T cells provoke a shift in the Th1/Th2 paradigm in immunity to infectious diseases. Trends Immunol 2002;23:450.
- Belkaid Y, Hoffmann KF, Mendez S, Kamhawi S, Udey MC, Wynn TA, Sacks DL: The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J Exp Med 2001;194:1497–1506.
- Ostrowski MA, Gu JX, Kovacs C, Freedman J, Luscher MA, MacDonald KS: 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-gamma and interleukin-10 responses. J Infect Dis 2001;184:1268–1278.
- Kullberg MC, Jankovic D, Gorelick PL, Caspar P, Letterio JJ, Cheever AW, Sher A: Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis. J Exp Med 2002;196:505–515.
- Khoo UY, Proctor IE, Macpherson AJ: CD4+ T cell down-regulation in human intestinal mucosa: Evidence for intestinal tolerance to luminal bacterial antigens. J Immunol 1997;158:3626–3634.
- Zuany-Amorim C, Sawicka E, Manlius C, Le Moine A, Brunet LR, Kemeny DM, Bowen G, Rook G, Walker C: Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells. Nat Med 2002;8:625–629.
- Arkwright PD, David TJ: Intradermal administration of a killed Mycobacterium vaccae suspension (SRL 172) is associated with improvement in atopic dermatitis in children with moderate-to-severe disease. J Allergy Clin Immunol 2001;107:531–534.
- Brady MS, Eckels DD, Lee F, Ree SY, Lee JS: Cytokine production by CD4+ T cells responding to antigen presentation by melanoma cells. Melanoma Res 1999;9:173–180.
- Seo N, Hayakawa S, Takigawa M, Tokura Y: Interleukin-10 expressed at early tumour sites induces subsequent generation of CD4(+) T-regulatory cells and systemic collapse of antitumour immunity. Immunology 2001;103:449–457.
- Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC: Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 2002;169:2756–2761.
- Vicari AP, Chiodoni C, Vaure C, Ait-Yahia S, Dercamp C, Matsos F, Reynard O, Taverne C, Merle P, Colombo MP, O’Garra A, Trinchieri G, Caux C: Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med 2002;196:541–549.
- Enk AH, Jonuleit H, Saloga J, Knop J: Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer 1997;73:309–316.
- Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T: Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: Their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001;182:18–32.
- Shevach EM: CD4+CD25+ suppressor T cells: More questions than answers. Nat Rev Immunol 2002;2:389–400.
- 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 2000;192:295–302.
- Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S: Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000;192:303–310.
- Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S: Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002;3:135–142.
- McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, Byrne MC: CD4(+)CD25(+) immunoregulatory T cells: Gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002;16:311–323.
- Zelenika D, Adams E, Humm S, Graca L, Thompson S, Cobbold SP, Waldmann H: Regulatory T cells overexpress a subset of Th2 gene transcripts. J Immunol 2002;168:1069–1079.
- Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler S: Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J Exp Med 2001;193:1303–1310.
- Papiernik M, do Carmo Leite-de-Moraes M, Pontoux C, Joret AM, Rocha B, Penit C, Dy M: T cell deletion induced by chronic infection with mouse mammary tumor virus spares a CD25-positive, IL-10-producing T cell population with infectious capacity. J Immunol 1997;158:4642–4653.
- Stephens LA, Mottet C, Mason D, Powrie F: Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur J Immunol 2001;31:1247–1254.
- Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa TC, Cumano A, Bandeira A: CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol 2001;166:3008–3018.
- Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F: An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 1999;190:995–1004.
- Pontoux C, Banz A, Papiernik M: Natural CD4 CD25(+) regulatory T cells control the burst of superantigen-induced cytokine production: The role of IL-10. Int Immunol 2002;14:233–239.
- Thornton AM, Shevach EM: CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998;188:287–296.
- Suri-Payer E, Cantor H: Differential cytokine requirements for regulation of autoimmune gastritis and colitis by CD4(+)CD25(+) T cells. J Autoimmun 2001;16:115–123.
- Apostolou I, Sarukhan A, Klein L, von Boehmer H: Origin of regulatory T cells with known specificity for antigen. Nat Immunol 2002;3:756–763.
- Buer J, Lanoue A, Franzke A, Garcia C, von Boehmer H, Sarukhan A: Interleukin 10 secretion and impaired effector function of major histocompatibility complex class II-restricted T cells anergized in vivo. J Exp Med 1998;187:177–183.
- Levings MK, Sangregorio R, Roncarolo MG: Human CD25+CD4+ T regulatory cells suppress naive and memory T-cell proliferation and can be expanded in vitro without loss of function. J Exp Med 2001;193:1295–1302.
- Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA: CD4+CD25high regulatory cells in human peripheral blood. J Immunol 2001;167:1245–1253.
- Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH: Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J Exp Med 2001;193:1285–1294.
- Taams LS, Smith J, Rustin MH, Salmon M, Poulter LW, Akbar AN: Human anergic/suppressive CD4(+)CD25(+) T cells: A highly differentiated and apoptosis-prone population. Eur J Immunol 2001;31:1122–1131.
- Ng WF, Duggan PJ, Ponchel F, Matarese G, Lombardi G, Edwards AD, Isaacs JD, Lechler RI: Human CD4(+)CD25(+) cells: A naturally occurring population of regulatory T cells. Blood 2001;98:2736–2744.
- 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 beta. J Exp Med 2001;194:629–644.
- Annunziato F, Cosmi L, Liotta F, Lazzeri E, Manetti R, Vanini V, Romagnani P, Maggi E, Romagnani S: Phenotype, localization, and mechanism of suppression of CD4(+)CD25(+) human thymocytes. J Exp Med 2002;196:379–387.
- Levings MK, Sangregorio R, Sartirana C, Moschin AL, Battaglia M, Orban PC, Roncarolo MG: Human CD25+CD4+ T suppressor cell clones produce TGF-b, but not IL-10, and are distinct from type 1 T regulatory cells. J Exp Med 2002;196:1335–1346.
- Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL: A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med 1996;183:2669–2674.
- Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, Shevach EM: CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 2002;196:237–246.
- Kingsley CI, Karim M, Bushell AR, Wood KJ: CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J Immunol 2002;168:1080–1086.
- Waldmann H, Cobbold S: How do monoclonal antibodies induce tolerance? A role for infectious tolerance? Annu Rev Immunol 1998;16:619–644.
- Zhang X, Izikson L, Liu L, Weiner HL: Activation of CD25(+)CD4(+) regulatory T cells by oral antigen administration. J Immunol 2001;167:4245–4253.
- Taams LS, Vukmanovic-Stejic M, Smith J, Dunne PJ, Fletcher JM, Plunkett FJ, Ebeling SB, Lombardi G, Rustin MH, Bijlsma JW, Lafeber FP, Salmon M, Akbar AN: Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells. Eur J Immunol 2002;32:1621–1630.
- Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G: Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 1-producing, contact-independent type 1-like regulatory T cells. J Exp Med 2002;196:247–253.
- Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH: Infectious tolerance: Human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells. J Exp Med 2002;196:255–260.
- Zelenika D, Adams E, Humm S, Lin CY, Waldmann H, Cobbold SP: The role of CD4+ T-cell subsets in determining transplantation rejection or tolerance. Immunol Rev 2001;182:164–179.
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