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TGF-β Function in Immune Suppression

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Book cover Negative Co-Receptors and Ligands

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 350))

Abstract

Transforming growth factor-β (TGF-β) has been shown to play an essential role in establishing immunological tolerance, yet recent studies have revealed the pro-inflammatory roles of TGF-β in inflammatory responses. TGF-β induces Foxp3-positive regulatory T cells (iTregs), while in the presence of IL-6, it induces pathogenic IL-17 producing Th17 cells. TGF-β inhibits the proliferation of T cells as well as cytokine production via Foxp3-dependent and independent mechanisms. On the one hand, little is known about molecular mechanisms involved in immune suppression via TGF-β; however, recent studies suggest that Smad2 as well as Smad3 play essential roles in Foxp3 induction and cytokine suppression, whereas Th17 differentiation is promoted via the Smad-independent pathway. Mutual suppression of signaling between TGF-β and inflammatory cytokines has been shown to be necessary for the balance of immunity and tolerance.

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References

  • Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N et al (2002) T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat Immunol 3:549–557

    PubMed  CAS  Google Scholar 

  • Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL (2003) Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278:1910–1914

    PubMed  CAS  Google Scholar 

  • Aluwihare P, Mu Z, Zhao Z, Yu D, Weinreb PH, Horan GS, Violette SM, Munger JS (2009) Mice that lack activity of alphavbeta6- and alphavbeta8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice. J Cell Sci 122:227–232

    PubMed  CAS  Google Scholar 

  • Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGF β activation. J Cell Sci 116:217–224

    PubMed  CAS  Google Scholar 

  • Bauquet AT, Jin H, Paterson AM, Mitsdoerffer M, Ho IC, Sharpe AH, Kuchroo VK (2009) The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat Immunol 10(2):167–175

    PubMed  CAS  Google Scholar 

  • Belladonna ML, Volpi C, Bianchi R, Vacca C, Orabona C, Pallotta MT, Boon L, Gizzi S, Fioretti MC, Grohmann U, Puccetti P (2008) Cutting edge: Autocrine TGF-beta sustains default tolerogenesis by IDO-competent dendritic cells. J Immunol 181(8):5194–5198

    PubMed  CAS  Google Scholar 

  • Bettelli E, Dastrange M, Oukka M (2005) Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci USA 102:5138–5143

    PubMed  CAS  Google Scholar 

  • Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    PubMed  CAS  Google Scholar 

  • Bommireddy R, Engle SJ, Ormsby I, Boivin GP, Babcock GF, Doetschman T (2004) Elimination of both CD4+ and CD8+ T cells but not B cells eliminates inflammation and prolongs the survival of TGFbeta1-deficient mice. Cell Immunol 232:96–104

    PubMed  CAS  Google Scholar 

  • Brabletz T, Pfeuffer I, Schorr E, Siebelt F, Wirth T, Serfling E (1993) Transforming growth factor β and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol Cell Biol 13:1155–1162

    PubMed  CAS  Google Scholar 

  • Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA (2007) IL-2 receptor beta-dependent STAT5 activation is required for the develop- ment of Foxp3+ regulatory T cells. J Immunol 178:280–290

    PubMed  CAS  Google Scholar 

  • Caretto D, Katzman SD, Villarino AV, Gallo E, Abbas AK (2010) Cutting edge: the Th1 response inhibits the generation of peripheral regulatory T cells. J Immunol 184(1):30–34

    PubMed  CAS  Google Scholar 

  • Chang H, Brown CW, Matzuk MM (2002) Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev 23:787–823

    PubMed  CAS  Google Scholar 

  • Chang JH, Kim YJ, Han SH, Kang CY (2009) IFN-gamma-STAT1 signal regulates the differentiation of inducible Treg: potential role for ROS-mediated apoptosis. Eur J Immunol 39(5):1241–1251

    PubMed  CAS  Google Scholar 

  • Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A, Rudensky AY (2009) CD4+regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326(5955):986–991

    PubMed  CAS  Google Scholar 

  • Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198(12):1875–1886

    PubMed  CAS  Google Scholar 

  • Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O'Shea JJ (2006) Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci USA 103:8137–8142

    PubMed  CAS  Google Scholar 

  • Chen ML, Yan BS, Bando Y, Kuchroo VK, Weiner HL (2008) Latency-associated peptide identifies a novel CD4+CD25+ regulatory T cell subset with TGFβ-mediated function and enhanced suppression of experimental autoimmune encephalomyelitis. J Immunol 180:7327–7337

    PubMed  CAS  Google Scholar 

  • Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, Jin HT, Min SY, Ju JH, Park KS, Cho YG, Yoon CH, Park SH, Sung YC, Kim HY (2006) STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol 176:5652–5661

    PubMed  CAS  Google Scholar 

  • Cottrez F, Groux H (2001) Regulation of TGF-beta response during T cell activation is modulated by IL-10. J Immunol 167:773–778

    PubMed  CAS  Google Scholar 

  • Das J, Ren G, Zhang L, Roberts AI, Zhao X, Bothwell AL, Van Kaer L, Shi Y, Das G (2009) Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med 206(13):2407–2416

    PubMed  CAS  Google Scholar 

  • Davidson TS, DiPaolo RJ, Andersson J, Shevach EM (2007) Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J Immunol 178:4022–4026

    PubMed  CAS  Google Scholar 

  • de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P et al (2008) Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med 205:1543

    PubMed  Google Scholar 

  • Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425:577–584

    PubMed  CAS  Google Scholar 

  • Diebold RJ, Eis MJ, Yin M, Ormsby I, Boivin GP, Darrow BJ, Saffitz JE, Doetschman T (1995) Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proc Natl Acad Sci USA 92:12215–12219

    PubMed  CAS  Google Scholar 

  • Ding A, Nathan CF, Graycar J, Derynck R, Stuehr DJ, Srimal S (1990) Macrophage deactivating factor and transforming growth factors-beta 1 -beta 2 and -beta 3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma. J Immunol 145:940–944

    PubMed  CAS  Google Scholar 

  • Dong C (2008) TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8(5):337–348

    PubMed  CAS  Google Scholar 

  • Eickelberg O, Pansky A, Koehler E, Bihl M, Tamm M, Hildebrand P, Perruchoud AP, Kashgarian M, Roth M (2001) Molecular mechanisms of TGF-(beta) antagonism by interferon (gamma) and cyclosporine A in lung fibroblasts. Faseb J 15:797–806

    PubMed  CAS  Google Scholar 

  • Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J Clin Invest 101:890–898

    PubMed  CAS  Google Scholar 

  • Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336

    PubMed  CAS  Google Scholar 

  • Geissmann F, Revy P, Regnault A, Lepelletier Y, Dy M, Brousse N, Amigorena S, Hermine O, Durandy A (1999) TGF-β1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol 162:4567–4575

    PubMed  CAS  Google Scholar 

  • Ghosh AK, Yuan W, Mori Y, Chen S, Varga J (2001) Antagonistic regulation of type I collagen gene expression by interferon-gamma and transforming growth factor-beta. Integration at the level of p300/CBP transcriptional coactivators. J Biol Chem 276:11041–11048

    PubMed  CAS  Google Scholar 

  • Glimcher LH, Murphy KM (2000) Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev 14:1693–1711

    PubMed  CAS  Google Scholar 

  • Gorelik L, Flavell RA (2000) Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12:171–181

    PubMed  CAS  Google Scholar 

  • Gorelik L, Constant S, Flavell RA (2002a) Mechanism of transforming growth factor β-induced inhibition of T helper type 1 differentiation. J Exp Med 195:1499–1505

    PubMed  CAS  Google Scholar 

  • Gorelik L, Fields PE, Flavell RA (2002b) Cutting edge: TGF-β inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol 165:4773–4777

    Google Scholar 

  • Govinden R, Bhoola KD (2003) Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther 98:257–265

    PubMed  CAS  Google Scholar 

  • Hannon GJ, Beach D (1994) p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371:257–261

    PubMed  CAS  Google Scholar 

  • Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132

    PubMed  CAS  Google Scholar 

  • He W, Dorn DC, Erdjument-Bromage H, Tempst P, Moore MA, Massague J (2006) Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway. Cell 125:929–941

    PubMed  CAS  Google Scholar 

  • Heath VL, Murphy EE, Crain C, Tomlinson MG, O'Garra A (2000) TGF-β1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression. Eur J Immunol 30:2639–2649

    PubMed  CAS  Google Scholar 

  • Horino J, Fujimoto M, Terabe F, Serada S, Takahashi T, Soma Y, Tanaka K, Chinen T, Yoshimura A, Nomura S, Kawase I, Hayashi N, Kishimoto T, Naka T (2008) Suppressor of cytokine signaling-1 ameliorates dextran sulfate sodium-induced colitis in mice. Int Immunol 20(6):753–762

    PubMed  CAS  Google Scholar 

  • Huber M, Brüstle A, Reinhard K, Guralnik A, Walter G, Mahiny A, von Löw E, Lohoff M (2008) IRF4 is essential for IL-21-mediated induction, amplification, and stabilization of the Th17 phenotype. Proc Natl Acad Sci USA 105(52):20846–20851

    PubMed  CAS  Google Scholar 

  • Huse M, Muir TW, Xu L, Chen YG, Kuriyan J, Massague J (2001) The TGF β receptor activation process: an inhibitor- to substrate-binding switch. Mol Cell 8:671–682

    PubMed  CAS  Google Scholar 

  • Ichiyama K, Yoshida H, Wakabayashi Y, Chinen T, Saeki K, Nakaya M, Takaesu G, Hori S, Yoshimura A, Kobayashi T (2008) Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat. J Biol Chem 283(25):17003–17008

    PubMed  CAS  Google Scholar 

  • Infante-Duarte C, Horton HF, Byrne MC, Kamradt T (2000) Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 165:6107–6115

    PubMed  CAS  Google Scholar 

  • Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133

    PubMed  CAS  Google Scholar 

  • Jaksits S, Kriehuber E, Charbonnier AS, Rappersberger K, Stingl G, Maurer D (1999) CD34+ cell-derived CD14+ precursor cells develop into Langerhans cells in a TGF-β1-dependent manner. J Immunol 163:4869–4877

    PubMed  CAS  Google Scholar 

  • Kim BG, Li C, Qiao W, Mamura M, Kasprzak B, Anver M, Wolfraim L, Hong S, Mushinski E, Potter M, Kim SJ, Fu XY, Deng C, Letterio JJ (2006) Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441:1015–1019

    PubMed  CAS  Google Scholar 

  • Kinjyo I, Inoue H, Hamano S, Fukuyama S, Yoshimura T, Koga K, Takaki H, Himeno K, Takaesu G, Kobayashi T, Yoshimura A (2006) Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-beta 1. J Exp Med 203(4):1021–1031

    PubMed  CAS  Google Scholar 

  • Korn T, Oukka M, Kuchroo V, Bettelli E (2007a) Th17 cells: effector T cells with inflammatory properties. Semin Immunol 19(6):362–371

    PubMed  CAS  Google Scholar 

  • Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK (2007b) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448:484–487

    PubMed  CAS  Google Scholar 

  • Kubo M, Hanada T, Yoshimura A (2003) Suppressors of cytokine signaling and immunity. Nat Immunol 4:1169–1176

    PubMed  CAS  Google Scholar 

  • Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S (1993) Transforming growth factor β1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 90:770–774

    PubMed  CAS  Google Scholar 

  • Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240

    PubMed  CAS  Google Scholar 

  • Laouar Y, Sutterwala FS, Gorelik L, Flavell RA (2005) Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. Nat Immunol 6:600–607

    PubMed  CAS  Google Scholar 

  • Letterio JJ, Geiser AG, Kulkarni AB, Dang H, Kong L, Nakabayashi T, Mackall CL, Gress RE, Roberts AB (1996) Autoimmunity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expressions II antigen expression. J Clin Invest 98:2109–2119

    PubMed  CAS  Google Scholar 

  • Li MO, Flavell RA (2008a) Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity 28(4):468–476

    PubMed  Google Scholar 

  • Li MO, Flavell RA (2008b) TGF-beta: a master of all T cell trades. Cell 134(3):392–404

    PubMed  CAS  Google Scholar 

  • Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006a) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146

    PubMed  CAS  Google Scholar 

  • Li MO, Sanjabi S, Flavell RA (2006b) Transforming growth factor-b controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25:455–471

    PubMed  CAS  Google Scholar 

  • Li MO, Wan YY, Flavell RA (2007) T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26(5):579–591

    PubMed  CAS  Google Scholar 

  • Ludviksson BR, Seegers D, Resnick AS, Strober W (2000) The effect of TGF-beta1 on immune responses of naive versus memory CD4+Th1/Th2 T cells. Eur J Immunol 30:2101–2111

    PubMed  CAS  Google Scholar 

  • Ma CS, Chew GYJ, Simpson N et al (2008) Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med 205:1551

    PubMed  CAS  Google Scholar 

  • Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234

    PubMed  CAS  Google Scholar 

  • Marie JC, Letterio JJ, Gavin M, Rudensky AY (2005) TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 201(7):1061–1067

    PubMed  CAS  Google Scholar 

  • Marie JC, Liggitt D, Rudensky AY (2006) Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25:441–454

    PubMed  CAS  Google Scholar 

  • Massague J (1998) TGF-beta signal transduction. Annu Rev Biochem 67:753–791

    PubMed  CAS  Google Scholar 

  • Matsumura Y, Kobayashi T, Ichiyama K, Yoshida R, Hashimoto M, Takimoto T, Tanaka K, Chinen T, Shichita T, Wyss-Coray T, Sato K, Yoshimura A (2007) Selective expansion of foxp3-positive regulatory T cells and immunosuppression by suppressors of cytokine signaling 3-deficient dendritic cells. J Immunol 179(4):2170–2179

    PubMed  CAS  Google Scholar 

  • McKarns SC, Schwartz RH, Kaminski NE (2004) Smad3 is essential for TGF-beta 1 to suppress IL-2 production and TCR-induced proliferation, but not IL-2-induced proliferation. J Immunol 172:4275–4284

    PubMed  CAS  Google Scholar 

  • Mempel TR, Pittet MJ, Khazaie K, Weninger W, Weissleder R, von Boehmer H, von Andrian UH (2006) Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25:129–141

    PubMed  CAS  Google Scholar 

  • Milner JD, Brenchley JM, Laurence A et al (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452:773

    PubMed  CAS  Google Scholar 

  • Mitani T, Terashima M, Yoshimura H, Nariai Y, Tanigawa Y (2005) TGF-beta1 enhances degradation of IFN-gamma-induced iNOS protein via proteasomes in RAW 264.7 cells. Nitric Oxide 13:78–87

    PubMed  CAS  Google Scholar 

  • Miyazono K, Maeda S, Imamura T (2004) Coordinate regulation of cell growth and differentiation by TGF-β superfamily and Runx proteins. Oncogene 23:4232–4237

    PubMed  CAS  Google Scholar 

  • Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765

    PubMed  CAS  Google Scholar 

  • Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317:256–260

    PubMed  CAS  Google Scholar 

  • Naiki Y, Michelsen KS, Zhang W, Chen S, Doherty TM, Arditi M (2005) Transforming growth factor-β differentially inhibits MyD88-dependent, but not TRAM- and TRIF-dependent, lipopolysaccharide-induced TLR4 signaling. J Biol Chem 280:5491–5495

    PubMed  CAS  Google Scholar 

  • Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, Strober W (2004) TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol 172(2):834–842

    PubMed  CAS  Google Scholar 

  • Nelson BJ, Ralph P, Green SJ, Nacy CA (1991) Differential susceptibility of activated macrophage cytotoxic effector reactions to the suppressive effects of transforming growth factor-beta 1. J Immunol 146:1849–1857

    PubMed  CAS  Google Scholar 

  • Nomura M, Li E (1998) Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 25:737–739

    Google Scholar 

  • Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, Dong C (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448:480–483

    PubMed  CAS  Google Scholar 

  • Ouaked N, Mantel PY, Bassin C, Burgler S, Siegmund K, Akdis CA, Schmidt-Weber CB (2009) Regulation of the foxp3 gene by the Th1 cytokines: the role of IL-27-induced STAT1. J Immunol 182(2):1041–1049

    PubMed  CAS  Google Scholar 

  • Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005a) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141

    PubMed  CAS  Google Scholar 

  • Park IK, Shultz LD, Letterio JJ, Gorham JD (2005b) TGF-beta1 inhibits T-bet induction by IFN-gamma in murine CD4+ T cells through the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1. J Immunol 175(9):5666–5674

    PubMed  CAS  Google Scholar 

  • Pesu M, Watford WT, Wei L, Xu L, Fuss I, Strober W, Andersson J, Shevach EM, Quezado M, Bouladoux N, Roebroek A, Belkaid Y, Creemers J, O'Shea JJ (2008) T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance. Nature 455:246–250

    PubMed  CAS  Google Scholar 

  • Polyak K, Kato JY, Solomon MJ, Sherr CJ, Massague J, Roberts JM, Koff A (1994) p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 8:9–22

    PubMed  CAS  Google Scholar 

  • Reardon C, McKay DM (2007) TGF-beta suppresses IFN-gamma-STAT1-dependent gene transcription by enhancing STAT1-PIAS1 interactions in epithelia but not monocytes/macrophages. J Immunol 178(7):4284–4295

    PubMed  CAS  Google Scholar 

  • Rubtsov YP, Rudensky AY (2007) TGFbeta signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol 7(6):443–453

    PubMed  CAS  Google Scholar 

  • Rudner LA, Lin JT, Park IK, Cates JM, Dyer DA, Franz DM, Fresnch MA, Duncan EM, White HD, Gorham JD (2003) Necroinflammatory liver disease in BALB/c background, TGF-beta 1-deficient mice requires CD4+ T cells. J Immunol 170:4785–4792

    PubMed  CAS  Google Scholar 

  • Ruegemer JJ, Ho SN, Augustine JA, Schlager JW, Bell MP, McKean DJ, Abraham RT (1990) Regulatory effects of transforming growth factor-beta on IL-2- and IL-4-dependent T cell-cycle progression. J Immunol 144(5):1767–1776

    PubMed  CAS  Google Scholar 

  • Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562

    PubMed  CAS  Google Scholar 

  • Samon JB, Champhekar A, Minter LM, Telfer JC, Miele L, Fauq A, Das P, Golde TE, Osborne BA (2008) Notch1 and TGFbeta1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells. Blood 112(5):1813–1821

    PubMed  CAS  Google Scholar 

  • Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D et al (1992) Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359:693–699

    PubMed  CAS  Google Scholar 

  • Strobl H, Knapp W (1999) TGF-β1 regulation of dendritic cells. Microbes Infect 1:1283–1289

    PubMed  CAS  Google Scholar 

  • Strobl H, Riedl E, Scheinecker C, Bello-Fernandez C, Pickl WF, Rappersberger K, Majdic O, Knapp W (1996) TGF-β1 promotes in vitro development of dendritic cells from CD34+ hemopoietic progenitors. J Immunol 157:1499–1507

    PubMed  CAS  Google Scholar 

  • Takaki H, Minoda Y, Koga K, Takaesu G, Yoshimura A, Kobayashi T (2006) TGF-beta1 suppresses IFN-gamma-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation. Genes Cells 11(8):871–882

    PubMed  CAS  Google Scholar 

  • Takaki H, Ichiyama K, Koga K, Chinen T, Takaesu G, Sugiyama Y, Kato S, Yoshimura A, Kobayashi T (2008) STAT6 Inhibits TGF-β-1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. J Biol Chem 283(22):14955–14962

    PubMed  CAS  Google Scholar 

  • Takimoto T, Wakabayashi Y, Sekiya T, Inoue N, Morita R, Ichiyama K, Takahashi R, Asakawa M, Muto G, Mori T, Hasegawa E, Shizuya S, Hara T, Nomura M, Yoshimura A (2010) Smad2 and Smad3 are redundantly essential for the TGF-β-mediated regulation of regulatory T plasticity and Th1 development. J Immunol 185 (2):842–855

    Google Scholar 

  • Tanaka K, Ichiyama K, Hashimoto M, Yoshida H, Takimoto T, Takaesu G, Torisu T, Hanada T, Yasukawa H, Fukuyama S, Inoue H, Nakanishi Y, Kobayashi T, Yoshimura A (2008) Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-gamma on STAT3 and Smads. J Immunol 180(6):3746–3756

    PubMed  CAS  Google Scholar 

  • Taylor AW (2009) Review of the activation of TGF-β in immunity. J Leukocyte Biol 85:29–33

    PubMed  CAS  Google Scholar 

  • Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M (2008) Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol 9(2):194–202

    PubMed  CAS  Google Scholar 

  • Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, Wang Y, Bernstein X, Huang X, Reichardt LF, Bluestone JA, Sheppard D (2007) αvβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449:361–365

    PubMed  CAS  Google Scholar 

  • Tzachanis D, Freeman GJ, Hirano N, van Puijenbroek AA, Delfs MW, Berezovskaya A, Nadler LM, Boussiotis VA (2001) Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat Immunol 2:1174–1182

    PubMed  CAS  Google Scholar 

  • Ulloa L, Doody J, Massague J (1999) Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 397:710–713

    PubMed  CAS  Google Scholar 

  • Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006a) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189

    PubMed  CAS  Google Scholar 

  • Veldhoen M, Hocking RJ, Flavell RA, Stockinger B (2006b) Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol 7(11):1151–1156

    PubMed  CAS  Google Scholar 

  • Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B (2008) Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9(12):1341–1346

    PubMed  CAS  Google Scholar 

  • Wan YY, Flavell RA (2007) 'Yin-Yang' functions of transforming growth factor-beta and T regulatory cells in immune regulation. Immunol Rev 220:199–213

    PubMed  CAS  Google Scholar 

  • Werner F, Jain MK, Feinberg MW, Sibinga NE, Pellacani A, Wiesel P, Chin MT, Topper JN, Perrella MA, Lee ME (2000) Transforming growth factor-β1 inhibition of macrophage activation is mediated via Smad3. J Biol Chem 275:36653–36658

    PubMed  CAS  Google Scholar 

  • Wolfraim LA, Walz TM, James Z, Fernandez T, Letterio JJ (2004) p21Cip1 and p27Kip1 act in synergy to alter the sensitivity of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2 responsiveness. J Immunol 173:3093–3102

    PubMed  CAS  Google Scholar 

  • Yamazaki S, Patel M, Harper A, Bonito A, Fukuyama H, Pack M, Tarbell KV, Talmor M, Ravetch JV, Inaba K, Steinman RM (2006) Effective expansion of alloantigen-specific Foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction. Proc Natl Acad Sci USA 103(8):2758–2763

    PubMed  CAS  Google Scholar 

  • Yamazaki S, Dudziak D, Heidkamp GF, Fiorese C, Bonito AJ, Inaba K, Nussenzweig MC, Steinman RM (2008) CD8+ CD205+ splenic dendritic cells are specialized to induce Foxp3+ regulatory T cells. J Immunol 181(10):6923–6933

    PubMed  CAS  Google Scholar 

  • Yang XO, Letterio JJ, Lechleider RJ, Chen L, Hayman R, Gu H, Roberts AB, Deng C (1999) Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-β. EMBO J 18:1280–1291

    PubMed  CAS  Google Scholar 

  • Yang Y, Ochando J, Yopp A, Bromberg JS, Ding Y (2005) IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation. J Immunol 174(5):2720–2729

    PubMed  CAS  Google Scholar 

  • Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363

    PubMed  CAS  Google Scholar 

  • Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS, Feng XH, Jetten AM, Dong C (2008) Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29(1):44–56

    PubMed  CAS  Google Scholar 

  • Yao Z, Kanno Y, Kerenyi M, Stephens G, Durant L, Watford WT, Laurence A, Robinson GW, Shevach EM, Moriggl R, Hennighausen L, Wu C, O'Shea JJ (2007) Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109:4368–4375

    PubMed  CAS  Google Scholar 

  • Yongzhong L, Zhang P, Li J, Kulkarni AB, Perruche S, Chen W (2008) A critical function for TGF-b signaling in the development of natural CD4+CD25+Foxp3+regulatory T cells. Nat Immunol 9:632–640

    Google Scholar 

  • Yoshimura A, Naka T, Kubo M (2007) SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 7:454–465

    PubMed  CAS  Google Scholar 

  • Yu L, Hebert MC, Zhang YE (2002) TGF-β receptor-activated p38 MAP kinase mediates Smad-independent TGF-β responses. EMBO J 21:3749–3759

    PubMed  CAS  Google Scholar 

  • Zhang Y, Zhang YY, Ogata M, Chen P, Harada A, Hashimoto S, Matsushima K (1999) Transforming growth factor-β1 polarizes murine hematopoietic progenitor cells to generate Langerhans cell-like dendritic cells through a monocyte/macrophage differentiation pathway. Blood 93:1208–1220

    PubMed  CAS  Google Scholar 

  • Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY (2010) Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463(7282):808–812

    PubMed  CAS  Google Scholar 

  • Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR (2008) TGF-beta-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453:236–240

    PubMed  CAS  Google Scholar 

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Acknowledgements

We thank F. Kotaki and N. Soma for manuscript preparation. This study was supported by Grants-in-Aid for Scientific Research (S) and for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), and CREST program by Japan Science and Technology Agency (JST).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Akihiko Yoshimura & Go Muto

  2. Japan Science and Technology Agency (JST), CREST, Chiyodau, Tokyo, 102-0075, Japan

    Akihiko Yoshimura

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  1. Akihiko Yoshimura
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  2. Go Muto
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Correspondence to Akihiko Yoshimura .

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Editors and Affiliations

  1. Emory Vaccine Center &, Yerkes National Primate Research Center, Emory University, Gatewood Rd. 954, Atlanta, 30329, Georgia, USA

    Rafi Ahmed

  2. Fac. Medicine, Dept. Medical Chemistry and Molecular, Kyoto University, Yoshida Konoe-cho, Kyoto, 606-8501, Japan

    Tasuku Honjo

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Yoshimura, A., Muto, G. (2010). TGF-β Function in Immune Suppression. In: Ahmed, R., Honjo, T. (eds) Negative Co-Receptors and Ligands. Current Topics in Microbiology and Immunology, vol 350. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_87

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