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Transforming growth factor-β: From its effect in T cell activation to a role in dominant tolerance

  • Ramireddy Bommireddy
  • Thomas Doetschman
Part of the Progress in Inflammation Research book series (PIR)

Abstract

Transforming growth factor (TGF)β1 is an important immunoregulatory cytokine involved in maintenance of self tolerance and T cell homeostasis [1]. It is produced by several immune and non-immune cell types and functions in both autocrine and paracrine manners [1]–[3]. Regulatory T cells (Treg) cells are the primary source of TGFβ1 for controlling autoimmune disease. Blockade of TGFβ signaling in T cells causes severe autoimmune disease in mice [4, 5]. However, TGFβ signaling in T cells under inflammatory conditions also causes the development of experimentally induced autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis (MS) disease [6]. This review focuses on recent findings concerning the function of TGFβ1 in T cells and immune tolerance, and it discusses implications of these findings for therapeutic intervention in autoimmune and inflammatory diseases.

Keywords

Transform Growth Factor Treg Cell Foxp3 Expression Experimentally Induce Autoimmune Encephalomyelitis Severe Autoimmune Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Bommireddy R, Doetschman T (2004) TGF-beta, T-cell tolerance and anti-CD3 therapy. Trends Mol Med 10: 3–9PubMedCrossRefGoogle Scholar
  2. 2.
    Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24: 99–146PubMedCrossRefGoogle Scholar
  3. 3.
    Schmidt-Weber CB, Blaser K (2004) Regulation and role of transforming growth fac tor-beta in immune tolerance induction and inflammation. Curr Opin Immunol 16: 709–716PubMedCrossRefGoogle Scholar
  4. 4.
    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: 441–454PubMedCrossRefGoogle Scholar
  5. 5.
    Li MO, Sanjabi S, Flavell RA (2006) Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and-independent mechanisms. Immunity 25: 455–471PubMedCrossRefGoogle Scholar
  6. 6.
    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: 235–238PubMedCrossRefGoogle Scholar
  7. 7.
    Chen W, Wahl SM (2002) TGF-beta: receptors, signaling pathways and autoimmunity. Curr Dir Autoimmun 5:62–91PubMedCrossRefGoogle Scholar
  8. 8.
    Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24: 677–688PubMedCrossRefGoogle Scholar
  9. 9.
    Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF (2004) Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25 T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172: 5149–5153PubMedGoogle Scholar
  10. 10.
    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: 1875–1886PubMedCrossRefGoogle Scholar
  11. 11.
    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: 1061–1067PubMedCrossRefGoogle Scholar
  12. 12.
    Zheng SG, Wang JH, Stohl W, Kim KS, Gray JD, Horwitz DA (2006) TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176: 3321–3329PubMedGoogle Scholar
  13. 13.
    Bommireddy R, Ormsby I, Yin M, Boivin GP, Babcock GF, Doetschman T (2003) TGFbeta1 inhibits Ca2+-calcineurin-mediated activation in thymocytes. J Immunol 170: 3645–3652PubMedGoogle Scholar
  14. 14.
    Bommireddy R, Saxena V, Ormsby I, Yin M, Boivin GP, Babcock GF, Singh RR, Doetschman T (2003) TGF-beta1 regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes. J Immunol 170: 4612–4622PubMedGoogle Scholar
  15. 15.
    Chen CH, Seguin-Devaux C, Burke NA, Oriss TB, Watkins SC, Clipstone N, Ray A (2003) Transforming growth factor beta blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation. J Exp Med 197: 1689–1699PubMedCrossRefGoogle Scholar
  16. 16.
    Wakefield LM, Roberts AB (2002) TGF-beta signaling: positive and negative effects on tumorigenesis. Curr Opin Genet Dev 12: 22–29PubMedCrossRefGoogle Scholar
  17. 17.
    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: 3093–3102PubMedGoogle Scholar
  18. 18.
    Chipuk JE, Bhat M, Hsing AY, Ma J, Danielpour D (2001) Bcl-xL blocks transforming growth factor-beta 1-induced apoptosis by inhibiting cytochrome c release and not by directly antagonizing Apaf-1-dependent caspase activation in prostate epithelial cells. J Biol Chem 276: 26614–26621PubMedCrossRefGoogle Scholar
  19. 19.
    Sung JL, Lin JT, Gorham JD (2003) CD28 co-stimulation regulates the effect of transforming growth factor-beta1 on the proliferation of naive CD4+ T cells. Int Immunopharmacol 3: 233–245PubMedCrossRefGoogle Scholar
  20. 20.
    Chen W, Jin W, Tian H, Sicurello P, Frank M, Orenstein JM, Wahl SM (2001) Requirement for transforming growth factor beta1 in controlling T cell apoptosis. J Exp Med 194: 439–453PubMedCrossRefGoogle Scholar
  21. 21.
    Khanna AK, Hosenpud JD (1999) Cyclosporine induces the expression of the cyclin inhibitor p21. Transplantation 67: 1262–1268PubMedCrossRefGoogle Scholar
  22. 22.
    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: 1121–1133PubMedCrossRefGoogle Scholar
  23. 23.
    Lin JT, Martin SL, Xia L, Gorham JD (2005) TGF-beta 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet. J Immunol 174: 5950–5958PubMedGoogle Scholar
  24. 24.
    Gorelik L, Fields PE, Flavell RA (2000) Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol 165: 4773–4777PubMedGoogle Scholar
  25. 25.
    Park IK, Shultz LD, Letterio JJ, Gorham JD (2005) 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: 5666–5674PubMedGoogle Scholar
  26. 26.
    Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu RJ, Jang IK, Gutkind JS, Shevach E, Gu H (2000) Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403: 216–220PubMedCrossRefGoogle Scholar
  27. 27.
    Krawczyk C, Bachmaier K, Sasaki T, Jones RG, Snapper SB, Bouchard D, Kozieradzki I, Ohashi PS, Alt FW, Penninger JM (2000) Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity 13: 463–473PubMedCrossRefGoogle Scholar
  28. 28.
    Zhu Y, Richardson JA, Parada LF, Graff JM (1998) Smad3 mutant mice develop metastatic colorectal cancer. Cell 94: 703–714PubMedCrossRefGoogle Scholar
  29. 29.
    Kim BG, Li C, Qiao W, Mamura M, Kasperczak 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: 1015–1019PubMedCrossRefGoogle Scholar
  30. 30.
    Conery AR, Cao Y, Thompson EA, Townsend CM Jr, Ko TC, Luo K (2004) Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol 6: 366–372PubMedCrossRefGoogle Scholar
  31. 30a.
    Bommireddy R, Doetschman T (2007) TGFβ1 and Treg cells: alliance for tolerance. Trends Mol Med 13; in press Google Scholar
  32. 31.
    Bommireddy R, Pathak LJ, Martin J, Ormsby I, Engle SJ, Boivin GP, Babcock GF, Eriksson AU, Singh RR, Doetschman T (2006) Self-antigen recognition by TGFbeta1-deficient T cells causes their activation and systemic inflammation. Lab Invest 86: 1008–1019PubMedCrossRefGoogle Scholar
  33. 32.
    Gorham JD, Lin JT, Sung JL, Rudner LA, French MA (2001) Genetic regulation of autoimmune disease: BALB/c background TGF-beta 1-deficient mice develop necroinflammatory IFN-gamma-dependent hepatitis. J Immunol 166: 6413–6422PubMedGoogle Scholar
  34. 33.
    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: 231–234PubMedCrossRefGoogle Scholar
  35. 34.
    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: 96–104PubMedCrossRefGoogle Scholar
  36. 35.
    Manzotti CN, Liu MK, Burke F, Dussably L, Zheng Y, Sansom DM (2006) Integration of CD28 and CTLA-4 function results in differential responses of T cells to CD80 and CD86. Eur J Immunol 36: 1413–1422PubMedCrossRefGoogle Scholar
  37. 36.
    Mamura M, Lee W, Sullivan TJ, Felici A, Sowers AL, Allison JP, Letterio JJ (2004) CD28 disruption exacerbates inflammation in TGFbeta1-/- mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-beta1. Blood 103: 4594–4601PubMedCrossRefGoogle Scholar
  38. 37.
    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: 12215–12219PubMedCrossRefGoogle Scholar
  39. 38.
    Boivin GP, Ormsby I, Jones-Carson J, O’Toole BA, Doetschman T (1997) Germ-free and barrier-raised TGF beta 1-deficient mice have similar inflammatory lesions. Transgenic Res 6: 197–202PubMedCrossRefGoogle Scholar
  40. 39.
    McKarns SC, Schwartz RH (2005) Distinct effects of TGF-beta 1 on CD4+ and CD8+ T cell survival, division, and IL-2 production: a role for T cell intrinsic Smad3. J Immunol 174: 2071–2083PubMedGoogle Scholar
  41. 40.
    Miyara M, Sakaguchi S (2007) Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 13: 108–116PubMedCrossRefGoogle Scholar
  42. 41.
    Fahlen L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA, Powrie F (2005) T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med 201: 737–746PubMedCrossRefGoogle Scholar
  43. 42.
    Gregg RK, Jain R, Schoenleber SJ, Divekar R, Bell JJ, Lee HH, Yu P, Zaghouani H (2004) A sudden decline in active membrane-bound TGF-beta impairs both T regulatory cell function and protection against autoimmune diabetes. J Immunol 173: 7308–7316PubMedGoogle Scholar
  44. 43.
    Carrier Y, Yuan J, Kuchroo VK, Weiner HL (2007) Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice. J Immunol 178: 179–185PubMedGoogle Scholar
  45. 44.
    Graca L, Chen TC, Le Moine A, Cobbold SP, Howie D, Waldmann H (2005) Dominant tolerance: activation thresholds for peripheral generation of regulatory T cells. Trends Immunol 26: 130–135PubMedCrossRefGoogle Scholar
  46. 45.
    Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA (2004) Natural and induced CD4+CD25+ cells educate CD4+CD25 cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol 172: 5213–5221PubMedGoogle Scholar
  47. 45a.
    Bommireddy R, Babcock GF, Singh RR, Doetschman T. TGFβ1 is not essential for natural Treg cell generation and maintenance. Clin Immunol; in revision Google Scholar
  48. 46.
    Pop SM, Wong CP, Culton DA, Clarke SH, Tisch R (2005) Single cell analysis shows decreasing FoxP3 and TGF-beta1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes. J Exp Med 201: 1333–1346PubMedCrossRefGoogle Scholar
  49. 47.
    Green EA, Gorelik L, McGregor CM, Tran EH, Flavell RA (2003) CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci USA 100: 10878–10883PubMedCrossRefGoogle Scholar
  50. 48.
    Nakamura K, Kitani A, Strober W (2001) Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194: 629–644PubMedCrossRefGoogle Scholar
  51. 49.
    Chen W, Jin W, Wahl SM (1998) Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells. J Exp Med 188: 1849–1857PubMedCrossRefGoogle Scholar
  52. 50.
    Belghith M, Bluestone JA, Barriot S, Megret J, Bach JF, Chatenoud L (2003) TGF-betadependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 9: 1202–1208PubMedCrossRefGoogle Scholar
  53. 51.
    Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Bluestone JA (2004) Distinct roles of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function. Eur J Immunol 34: 2996–3005PubMedCrossRefGoogle Scholar
  54. 52.
    Macian F, Garcia-Cozar F, Im SH, Horton HF, Byrne MC, Rao A (2002) Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109: 719–731PubMedCrossRefGoogle Scholar
  55. 53.
    Wohlfert EA, Gorelik L, Mittler R, Flavell RA, Clark RB (2006) Cutting Edge: Deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGFbeta sensitivity in vitro and in vivo. J Immunol 176: 1316–1320PubMedGoogle Scholar
  56. 54.
    Chatenoud L (2005) CD3-specific antibodies restore self-tolerance: mechanisms and clinical applications. Curr Opin Immunol 17: 632–637PubMedCrossRefGoogle Scholar
  57. 55.
    Ochi H, Abraham M, Ishikawa H, Frenkel D, Yang K, Basso AS, Wu H, Chen ML, Gandhi R, Miller A, Maron R, Weiner HL (2006) Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4(+)CD25(™)LAP(+) T cells. Nat Med 12: 627–635PubMedCrossRefGoogle Scholar
  58. 56.
    Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, Santamaria P, Locksley RM, Krummel MF, Bluestone JA (2006) Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 7: 83–92PubMedCrossRefGoogle Scholar
  59. 57.
    Oderup C, Cederbom L, Makowska A, Cilio CM, Ivars F (2006) Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression. Immunology 118: 240–249PubMedCrossRefGoogle Scholar
  60. 58.
    Hryniewicz A, Boasso A, Edghill-Smith Y, Vaccari M, Fuchs D, Venzon D, Nacsa J, Betts MR, Tsai WP, Heraud JM et al (2006) CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques. Blood 108: 3834–3842PubMedCrossRefGoogle Scholar
  61. 59.
    Lyakh LA, Sanford M, Chekol S, Young HA, Roberts AB (2005) TGF-beta and vitamin D3 utilize distinct pathways to suppress IL-12 production and modulate rapid differentiation of human monocytes into CD83+ dendritic cells. J Immunol 174: 2061–2070PubMedGoogle Scholar
  62. 60.
    Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, Candeloro P, Belladonna ML, Bianchi R, Fioretti MC, Puccetti P (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3: 1097–1101PubMedCrossRefGoogle Scholar
  63. 61.
    Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22: 633–642PubMedCrossRefGoogle Scholar
  64. 62.
    Mellor AL, Baban B, Chandler P, Marshall B, Jhaver K, Hansen A, Koni PA, Iwashima M, Munn DH (2003) Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J Immunol 171: 1652–1655PubMedGoogle Scholar
  65. 63.
    Tivol EA, Boyd SD, McKeon S, Borriello F, Nickerson P, Strom TB, Sharpe AH (1997) CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice. J Immunol 158: 5091–5094PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2008

Authors and Affiliations

  • Ramireddy Bommireddy
    • 1
    • 2
  • Thomas Doetschman
    • 1
    • 3
    • 4
  1. 1.BIO5 InstituteUniversity of ArizonaTucsonUSA
  2. 2.Department of ImmunobiologyUniversity of ArizonaTucsonUSA
  3. 3.Department of Cell Biology and AnatomyUniversity of ArizonaTucsonUSA
  4. 4.Arizona Cancer CenterUniversity of ArizonaTucsonUSA

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