Journal of Clinical Immunology

, Volume 28, Issue 6, pp 647–659 | Cite as

TGF-β and Regulatory T Cell in Immunity and Autoimmunity

Article

Abstract

Introduction

The immune response is controlled by several inhibitory mechanisms. These mechanisms include regulatory T cells, which exist in multiple classes. Notable among these are Foxp3-expressing regulatory T cells (Treg), NKT cells, and Tr1 cells. Common to these mechanisms are inhibitory cytokines such as interleukin-10 and transforming growth factor-beta (TGF-β). TGF-β and Foxp3-expressing Treg cells are critical in maintaining self-tolerance and immune homeostasis.

Discussions

The immune suppressive functions of TGF-β and Treg cells are widely acknowledged and extensively studied. Nonetheless, recent studies revealed the positive roles for TGF-β and Treg cells in shaping the immune system and the inflammatory responses. In this paper, we will discuss the role of these mechanisms in the control of immunity and autoimmunity and the mechanisms that underlie how these molecules control these responses.

Keywords

TGF-β Treg NKT IL-10 

References

  1. 1.
    Gershon RK. A disquisition on suppressor T cells. Transplant Rev. 1975;26:170–85.PubMedGoogle Scholar
  2. 2.
    Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med. 2000;342:1350–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Annes JP, Chen Y, Munger JS, Rifkin DB. Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1. J Cell Biol. 2004;165:723–34.PubMedCrossRefGoogle Scholar
  4. 4.
    Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFbeta activation. J Cell Sci. 2003;116:217–24.PubMedCrossRefGoogle Scholar
  5. 5.
    Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell. 1998;93:1159–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, et al. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell. 1999;96:319–28.PubMedCrossRefGoogle Scholar
  7. 7.
    Yehualaeshet T, O’Connor R, Green-Johnson J, Mai S, Silverstein R, Murphy-Ullrich JE, Khalil N. Activation of rat alveolar macrophage-derived latent transforming growth factor beta-1 by plasmin requires interaction with thrombospondin-1 and its cell surface receptor, CD36. Am J Pathol. 1999;155:841–51.PubMedGoogle Scholar
  8. 8.
    Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol. 1998;16:137–61.PubMedCrossRefGoogle Scholar
  9. 9.
    Green EA, Gorelik L, McGregor CM, Tran EH, Flavell RA. 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 U S A. 2003;100:10878–83.PubMedCrossRefGoogle Scholar
  10. 10.
    Massague J. TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753–91.PubMedCrossRefGoogle Scholar
  11. 11.
    Huse M, Muir TW, Xu L, Chen YG, Kuriyan J, Massague J. The TGF beta receptor activation process: an inhibitor- to substrate-binding switch. Mol Cell. 2001;8:671–82.PubMedCrossRefGoogle Scholar
  12. 12.
    Inman GJ, Nicolas FJ, Hill CS. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Mol Cell. 2002;10:283–94.PubMedCrossRefGoogle Scholar
  13. 13.
    Johnson K, Kirkpatrick H, Comer A, Hoffmann FM, Laughon A. Interaction of Smad complexes with tripartite DNA-binding sites. J Biol Chem. 1999;274:20709–16.PubMedCrossRefGoogle Scholar
  14. 14.
    Shi Y, Wang YF, Jayaraman L, Yang H, Massague J, Pavletich NP. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell. 1998;94:585–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Zawel L, Dai JL, Buckhaults P, Zhou S, Kinzler KW, Vogelstein B, Kern SE. Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell. 1998;1:611–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Engel ME, McDonnell MA, Law BK, Moses HL. Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J Biol Chem. 1999;274:37413–20.PubMedCrossRefGoogle Scholar
  17. 17.
    Yu L, Hebert MC, Zhang YE. TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J. 2002;21:3749–59.PubMedCrossRefGoogle Scholar
  18. 18.
    Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425:577–84.PubMedCrossRefGoogle Scholar
  19. 19.
    Blanchette F, Rivard N, Rudd P, Grondin F, Attisano L, Dubois CM. Cross-talk between the p42/p44 MAP kinase and Smad pathways in transforming growth factor beta 1-induced furin gene transactivation. J Biol Chem. 2001;276:33986–94.PubMedCrossRefGoogle Scholar
  20. 20.
    Funaba M, Zimmerman CM, Mathews LS. Modulation of Smad2-mediated signaling by extracellular signal-regulated kinase. J Biol Chem. 2002;277:41361–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Kretzschmar M, Doody J, Timokhina I, Massague J. A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev. 1999;13:804–16.PubMedCrossRefGoogle Scholar
  22. 22.
    Choy L, Derynck R. The type II transforming growth factor (TGF)-beta receptor-interacting protein TRIP-1 acts as a modulator of the TGF-beta response. J Biol Chem. 1998;273:31455–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Griswold-Prenner I, Kamibayashi C, Maruoka EM, Mumby MC, Derynck R. Physical and functional interactions between type I transforming growth factor beta receptors and Balpha, a WD-40 repeat subunit of phosphatase 2A. Mol Cell Biol. 1998;18:6595–604.PubMedGoogle Scholar
  24. 24.
    McGonigle S, Beall MJ, Pearce EJ. Eukaryotic initiation factor 2 alpha subunit associates with TGF beta receptors and 14–3–3 epsilon and acts as a modulator of the TGF beta response. Biochemistry. 2002;41:579–87.PubMedCrossRefGoogle Scholar
  25. 25.
    Chen CH, Seguin-Devaux C, Burke NA, Oriss TB, Watkins SC, Clipstone N, Ray A. Transforming growth factor beta blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation. J Exp Med. 2003;197:1689–19.PubMedCrossRefGoogle Scholar
  26. 26.
    Gorelik L, Constant S, Flavell RA. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med. 2002;195:1499–505.PubMedCrossRefGoogle Scholar
  27. 27.
    Gorelik L, Fields PE, Flavell RA. Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol. 2000;165:4773–7.PubMedGoogle Scholar
  28. 28.
    Lin JT, Martin SL, Xia L, Gorham JD. TGF-beta1 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. 2005;174:5950–8.PubMedGoogle Scholar
  29. 29.
    Thomas DA, Massague J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8:369–80.PubMedCrossRefGoogle Scholar
  30. 30.
    Gershon RK, Kondo K. Infectious immunological tolerance. Immunology. 1971;21:903–14.PubMedGoogle Scholar
  31. 31.
    Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology. 1970;18:723–37.PubMedGoogle Scholar
  32. 32.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155:1151–64.PubMedGoogle Scholar
  33. 33.
    Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–62.PubMedCrossRefGoogle Scholar
  34. 34.
    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;194:629–44.PubMedCrossRefGoogle Scholar
  35. 35.
    Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6:345–52.PubMedCrossRefGoogle Scholar
  36. 36.
    Shevach EM. Regulatory T cells in autoimmmunity*. Annu Rev Immunol. 2000;18:423–49.PubMedCrossRefGoogle Scholar
  37. 37.
    Shevach EM. CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol. 2002;2:389–400.PubMedGoogle Scholar
  38. 38.
    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;389:737–42.PubMedCrossRefGoogle Scholar
  39. 39.
    Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immunol Rev. 2001;182:68–79.PubMedCrossRefGoogle Scholar
  40. 40.
    Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A, Barthlott T, Stockinger B, Wraith DC, O’Garra A. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol. 2004;172:5986–93.PubMedGoogle Scholar
  41. 41.
    Faria AM, Weiner HL. Oral tolerance. Immunol Rev. 2005;206:232–59.PubMedCrossRefGoogle Scholar
  42. 42.
    Weiner HL. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev. 2001;182:207–14.PubMedCrossRefGoogle Scholar
  43. 43.
    Stassen M, Fondel S, Bopp T, Richter C, Muller C, Kubach J, Becker C, Knop J, Enk AH, Schmitt S, et al. Human CD25+ regulatory T cells: two subsets defined by the integrins alpha 4 beta 7 or alpha 4 beta 1 confer distinct suppressive properties upon CD4+ T helper cells. Eur J Immunol. 2004;34:1303–11.PubMedCrossRefGoogle Scholar
  44. 44.
    Kehrl JH, Roberts AB, Wakefield LM, Jakowlew S, Sporn MB, Fauci AS. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol. 1986;137:3855–60.PubMedGoogle Scholar
  45. 45.
    Kehrl JH, Wakefield LM, Roberts AB, Jakowlew S, Alvarez-Mon M, Derynck R, Sporn MB, Fauci AS. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986;163:1037–50.PubMedCrossRefGoogle Scholar
  46. 46.
    Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993;90:770–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992;359:693–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Cazac BB, Roes J. TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo. Immunity. 2000;13:443–51.PubMedCrossRefGoogle Scholar
  49. 49.
    Datto MB, Frederick JP, Pan L, Borton AJ, Zhuang Y, Wang XF. Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol Cell Biol. 1999;19:2495–504.PubMedGoogle Scholar
  50. 50.
    Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity. 2000;12:171–81.PubMedCrossRefGoogle Scholar
  51. 51.
    Laouar Y, Sutterwala FS, Gorelik L, Flavell RA. Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. Nat Immunol. 2005;6:600–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Lucas PJ, Kim SJ, Melby SJ, Gress RE. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor beta II receptor. J Exp Med. 2000;191:1187–96.PubMedCrossRefGoogle Scholar
  53. 53.
    Nakao A, Miike S, Hatano M, Okumura K, Tokuhisa T, Ra C, Iwamoto I. Blockade of transforming growth factor beta/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity. J Exp Med. 2000;192:151–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Yang X, Letterio JJ, Lechleider RJ, Chen L, Hayman R, Gu H, Roberts AB, Deng C. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J. 1999;18:1280–91.PubMedCrossRefGoogle Scholar
  55. 55.
    Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146.PubMedCrossRefGoogle Scholar
  56. 56.
    Brabletz T, Pfeuffer I, Schorr E, Siebelt F, Wirth T, Serfling E. Transforming growth factor beta and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol Cell Biol. 1993;13:1155–62.PubMedGoogle Scholar
  57. 57.
    McKarns SC, Schwartz RH, Kaminski NE. Smad3 is essential for TGF-beta 1 to suppress IL-2 production and TCR-induced proliferation, but not IL-2-induced proliferation. J Immunol. 2004;172:4275–84.PubMedGoogle Scholar
  58. 58.
    Tzachanis D, Freeman GJ, Hirano N, van Puijenbroek AA, Delfs MW, Berezovskaya A, Nadler LM, Boussiotis VA. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat Immunol. 2001;2:1174–82.PubMedCrossRefGoogle Scholar
  59. 59.
    Murphy KM, Reiner SL. The lineage decisions of helper T cells. Nat Rev Immunol. 2002;2:933–44.PubMedCrossRefGoogle Scholar
  60. 60.
    Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–73.PubMedCrossRefGoogle Scholar
  61. 61.
    Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005;6:1133–41.PubMedCrossRefGoogle Scholar
  62. 62.
    Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006;203:2271–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Gorelik L, Flavell RA. Transforming growth factor-beta in T-cell biology. Nat Rev Immunol. 2002;2:46–53.PubMedCrossRefGoogle Scholar
  64. 64.
    Gorham JD, Guler ML, Fenoglio D, Gubler U, Murphy KM. Low dose TGF-beta attenuates IL-12 responsiveness in murine Th cells. J Immunol. 1998;161:1664–70.PubMedGoogle Scholar
  65. 65.
    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;30:2639–49.PubMedCrossRefGoogle Scholar
  66. 66.
    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;30:2101–11.PubMedCrossRefGoogle Scholar
  67. 67.
    Li MO, Sanjabi S, Flavell RA. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity. 2006;25:455–71.PubMedCrossRefGoogle Scholar
  68. 68.
    Sad S, Mosmann TR. Single IL-2-secreting precursor CD4 T cell can develop into either Th1 or Th2 cytokine secretion phenotype. J Immunol. 1994;153:3514–22.PubMedGoogle Scholar
  69. 69.
    Kitani A, Fuss I, Nakamura K, Kumaki F, Usui T, Strober W. Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-beta1-mediated fibrosis. J Exp Med. 2003;198:1179–88.PubMedCrossRefGoogle Scholar
  70. 70.
    Ahmadzadeh M, Rosenberg SA. TGF-beta1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol. 2005;174:5215–23.PubMedGoogle Scholar
  71. 71.
    Bonig H, Banning U, Hannen M, Kim YM, Verheyen J, Mauz-Korholz C, Korholz D. Transforming growth factor-beta1 suppresses interleukin-15-mediated interferon-gamma production in human T lymphocytes. Scand J Immunol. 1999;50:612–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Ranges GE, Figari IS, Espevik T, Palladino MA Jr. Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. J Exp Med. 1987;166:991–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Smyth MJ, Strobl SL, Young HA, Ortaldo JR, Ochoa AC. Regulation of lymphokine-activated killer activity and pore-forming protein gene expression in human peripheral blood CD8+ T lymphocytes. Inhibition by transforming growth factor-beta. J Immunol. 1991;146:3289–97.PubMedGoogle Scholar
  74. 74.
    Mempel TR, Pittet MJ, Khazaie K, Weninger W, Weissleder R, von Boehmer H, von Andrian UH. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity. 2006;25:129–41.PubMedCrossRefGoogle Scholar
  75. 75.
    Rudner LA, Lin JT, Park IK, Cates JM, Dyer DA, Franz DM, French MA, Duncan EM, White HD, Gorham JD. Necroinflammatory liver disease in BALB/c background, TGF-beta 1-deficient mice requires CD4+ T cells. J Immunol. 2003;170:4785–92.PubMedGoogle Scholar
  76. 76.
    Letterio JJ, Geiser AG, Kulkarni AB, Dang H, Kong L, Nakabayashi T, Mackall CL, Gress RE, Roberts AB. Autoimmunity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expression. J Clin Invest. 1996;98:2109–19.PubMedCrossRefGoogle Scholar
  77. 77.
    Marie JC, Liggitt D, Rudensky AY. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity. 2006;25:441–54.PubMedCrossRefGoogle Scholar
  78. 78.
    Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med. 2001;7:1118–22.PubMedCrossRefGoogle Scholar
  79. 79.
    Leveen P, Larsson J, Ehinger M, Cilio CM, Sundler M, Sjostrand LJ, Holmdahl R, Karlsson S. Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood. 2002;100:560–8.PubMedCrossRefGoogle Scholar
  80. 80.
    Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100:655–69.PubMedCrossRefGoogle Scholar
  81. 81.
    Marie JC, Letterio JJ, Gavin M, Rudensky AY. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+regulatory T cells. J Exp Med. 2005;201:1061–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H, Khazaie K. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci U S A. 2005;102:419–24.PubMedCrossRefGoogle Scholar
  83. 83.
    Fahlen L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA, Powrie F. T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med. 2005;201:737–46.PubMedCrossRefGoogle Scholar
  84. 84.
    Li MO, Wan YY, Flavell RA. T cell-produced transforming growth factor-beta1 controls t cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity. 2007;26:579–91.PubMedCrossRefGoogle Scholar
  85. 85.
    Gray JD, Hirokawa M, Horwitz DA. The role of transforming growth factor beta in the generation of suppression: an interaction between CD8+T and NK cells. J Exp Med. 1994;180:1937–42.PubMedCrossRefGoogle Scholar
  86. 86.
    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;166:7282–9.PubMedGoogle Scholar
  87. 87.
    Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004;172:5149–53.PubMedGoogle Scholar
  88. 88.
    Rich S, Seelig M, Lee HM, Lin J. Transforming growth factor beta 1 costimulated growth and regulatory function of staphylococcal enterotoxin B-responsive CD8+T cells. J Immunol. 1995;155:609–18.PubMedGoogle Scholar
  89. 89.
    Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM. 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. 2003;198:1875–86.PubMedCrossRefGoogle Scholar
  90. 90.
    Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005;22:329–41.PubMedCrossRefGoogle Scholar
  91. 91.
    Wan YY, Flavell RA. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci U S A. 2005;102:5126–31.PubMedCrossRefGoogle Scholar
  92. 92.
    Peng Y, Laouar Y, Li MO, Green EA, Flavell RA. TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci U S A. 2004;101:4572–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Schramm C, Protschka M, Kohler HH, Podlech J, Reddehase MJ, Schirmacher P, Galle PR, Lohse AW, Blessing M. Impairment of TGF-beta signaling in T cells increases susceptibility to experimental autoimmune hepatitis in mice. Am J Physiol Gastrointest Liver Physiol. 2003;284:G525–535.PubMedGoogle Scholar
  94. 94.
    Huber S, Schramm C, Lehr HA, Mann A, Schmitt S, Becker C, Protschka M, Galle PR, Neurath MF, Blessing M. Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+T cells. J Immunol. 2004;173:6526–31.PubMedGoogle Scholar
  95. 95.
    Mamura M, Lee W, Sullivan TJ, Felici A, Sowers AL, Allison JP, Letterio JJ. CD28 disruption exacerbates inflammation in Tgf-beta1−/− mice: in vivo suppression by CD4+CD25+regulatory T cells independent of autocrine TGF-beta1. Blood. 2004;103:4594–601.PubMedCrossRefGoogle Scholar
  96. 96.
    Lee HM, Rich S. Differential activation of CD8+T cells by transforming growth factor-beta 1. J Immunol. 1993;151:668–77.PubMedGoogle Scholar
  97. 97.
    Gray JD, Liu T, Huynh N, Horwitz DA. Transforming growth factor beta enhances the expression of CD154 (CD40L) and production of tumor necrosis factor alpha by human T lymphocytes. Immunol Lett. 2001;78:83–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Chung EJ, Choi SH, Shim YH, Bang YJ, Hur KC, Kim CW. Transforming growth factor-beta induces apoptosis in activated murine T cells through the activation of caspase 1-like protease. Cell Immunol. 2000;204:46–54.PubMedCrossRefGoogle Scholar
  99. 99.
    Sillett HK, Cruickshank SM, Southgate J, Trejdosiewicz LK. Transforming growth factor-beta promotes ‘death by neglect’ in post-activated human T cells. Immunology. 2001;102:310–6.PubMedCrossRefGoogle Scholar
  100. 100.
    Chen W, Jin W, Tian H, Sicurello P, Frank M, Orenstein JM, Wahl SM. Requirement for transforming growth factor beta1 in controlling T cell apoptosis. J Exp Med. 2001;194:439–53.PubMedCrossRefGoogle Scholar
  101. 101.
    Genestier L, Kasibhatla S, Brunner T, Green DR. Transforming growth factor beta1 inhibits Fas ligand expression and subsequent activation-induced cell death in T cells via downregulation of c-Myc. J Exp Med. 1999;189:231–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24:179–89.PubMedCrossRefGoogle Scholar
  103. 103.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441:231–4.PubMedCrossRefGoogle Scholar
  104. 104.
    Veldhoen M, Hocking RJ, Flavell RA, Stockinger B. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol. 2006;7:1151–6.PubMedCrossRefGoogle Scholar
  105. 105.
    Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 2006;24:677–88.PubMedCrossRefGoogle Scholar
  106. 106.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8.PubMedCrossRefGoogle Scholar
  107. 107.
    Sakaguchi S, Takahashi T, Nishizuka Y. Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J Exp Med. 1982;156:1577–86.PubMedCrossRefGoogle Scholar
  108. 108.
    Sakaguchi S, Takahashi T, Nishizuka Y. Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer. J Exp Med. 1982;156:1565–76.PubMedCrossRefGoogle Scholar
  109. 109.
    Fontenot JD, Dooley JL, Farr AG, Rudensky AY. Developmental regulation of Foxp3 expression during ontogeny. J Exp Med. 2005;202:901–6.PubMedCrossRefGoogle Scholar
  110. 110.
    Schwartz RH. Natural regulatory T cells and self-tolerance. Nat Immunol. 2005;6:327–30.PubMedCrossRefGoogle Scholar
  111. 111.
    Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27:20–1.PubMedCrossRefGoogle Scholar
  112. 112.
    Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27:68–73.PubMedCrossRefGoogle Scholar
  113. 113.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.PubMedCrossRefGoogle Scholar
  114. 114.
    Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+T regulatory cells. Nat Immunol. 2003;4:337–42.PubMedCrossRefGoogle Scholar
  115. 115.
    Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27:18–20.PubMedCrossRefGoogle Scholar
  116. 116.
    Chang X, Gao JX, Jiang Q, Wen J, Seifers N, Su L, Godfrey VL, Zuo T, Zheng P, Liu Y. The Scurfy mutation of FoxP3 in the thymus stroma leads to defective thymopoiesis. J Exp Med. 2005;202:1141–51.PubMedCrossRefGoogle Scholar
  117. 117.
    Liston A, Farr AG, Chen Z, Benoist C, Mathis D, Manley NR, Rudensky AY. Lack of Foxp3 function and expression in the thymic epithelium. J Exp Med. 2007;204:475–80.PubMedCrossRefGoogle Scholar
  118. 118.
    Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8:191–7.PubMedCrossRefGoogle Scholar
  119. 119.
    Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 2007;8:277–84.PubMedCrossRefGoogle Scholar
  120. 120.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+regulatory T cells. Nat Immunol. 2003;4:330–6.PubMedCrossRefGoogle Scholar
  121. 121.
    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;188:287–96.PubMedCrossRefGoogle Scholar
  122. 122.
    D’Cruz LM, Klein L. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol. 2005;6:1152–9.PubMedCrossRefGoogle Scholar
  123. 123.
    Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6:1142–51.PubMedCrossRefGoogle Scholar
  124. 124.
    Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ. Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med. 2002;196:851–7.PubMedCrossRefGoogle Scholar
  125. 125.
    Barthlott T, Moncrieffe H, Veldhoen M, Atkins CJ, Christensen J, O’Garra A, Stockinger B. CD25+CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production. Int Immunol. 2005;17:279–88.PubMedCrossRefGoogle Scholar
  126. 126.
    de la Rosa M, Rutz S, Dorninger H, Scheffold A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur J Immunol. 2004;34:2480–8.PubMedCrossRefGoogle Scholar
  127. 127.
    Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol. 2007;8:1353–62.PubMedCrossRefGoogle Scholar
  128. 128.
    Egen JG, Allison JP. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity. 2002;16:23–35.PubMedCrossRefGoogle Scholar
  129. 129.
    Slavik JM, Hutchcroft JE, Bierer BE. CD28/CTLA-4 and CD80/CD86 families: signaling and function. Immunol Res. 1999;19:1–24.PubMedCrossRefGoogle Scholar
  130. 130.
    Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515–48.PubMedCrossRefGoogle Scholar
  131. 131.
    Boden E, Tang Q, Bour-Jordan H, Bluestone JA. The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ regulatory T cells. Novartis Found Symp. 2003;252:55–63. (discussion 63–6, 106–14).PubMedCrossRefGoogle Scholar
  132. 132.
    Read S, Greenwald R, Izcue A, Robinson N, Mandelbrot D, Francisco L, Sharpe AH, Powrie F. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J Immunol. 2006;177:4376–83.PubMedGoogle Scholar
  133. 133.
    Uhlig HH, Coombes J, Mottet C, Izcue A, Thompson C, Fanger A, Tannapfel A, Fontenot JD, Ramsdell F, Powrie F. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol. 2006;177:5852–60.PubMedGoogle Scholar
  134. 134.
    Kamanaka M, Kim ST, Wan YY, Sutterwala FS, Lara-Tejero M, Galan JE, Harhaj E, Flavell RA. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 2006;25:941–52.PubMedCrossRefGoogle Scholar
  135. 135.
    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.PubMedCrossRefGoogle Scholar
  136. 136.
    Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML, Fioretti MC, Alegre ML, Puccetti P. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003;4:1206–12.PubMedCrossRefGoogle Scholar
  137. 137.
    Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A, Lafaille JJ, Dustin ML. Regulatory T cells inhibit stable contacts between CD4+T cells and dendritic cells in vivo. J Exp Med. 2006;203:505–11.PubMedCrossRefGoogle Scholar
  138. 138.
    Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005;6:1219–27.PubMedCrossRefGoogle Scholar
  139. 139.
    Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007;120:744–50. (quiz 751–2).PubMedCrossRefGoogle Scholar
  140. 140.
    Miura Y, Thoburn CJ, Bright EC, Phelps ML, Shin T, Matsui EC, Matsui WH, Arai S, Fuchs EJ, Vogelsang GB, et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood. 2004;104:2187–93.PubMedCrossRefGoogle Scholar
  141. 141.
    Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S. Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood. 2005;105:735–41.PubMedCrossRefGoogle Scholar
  142. 142.
    Huan J, Culbertson N, Spencer L, Bartholomew R, Burrows GG, Chou YK, Bourdette D, Ziegler SF, Offner H, Vandenbark AA. Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res. 2005;81:45–52.PubMedCrossRefGoogle Scholar
  143. 143.
    Lyon MF, Peters J, Glenister PH, Ball S, Wright E. The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott–Aldrich syndrome. Proc Natl Acad Sci USA. 1990;87:2433–7.PubMedCrossRefGoogle Scholar
  144. 144.
    Ono M, Shimizu J, Miyachi Y, Sakaguchi S. Control of autoimmune myocarditis and multiorgan inflammation by glucocorticoid-induced TNF receptor family-related protein(high), Foxp3-expressing CD25+ and CD25− regulatory T cells. J Immunol. 2006;176:4748–56.PubMedGoogle Scholar
  145. 145.
    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;192:303–10.PubMedCrossRefGoogle Scholar
  146. 146.
    Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature. 2007;445:766–70.PubMedCrossRefGoogle Scholar
  147. 147.
    Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA, Rudensky AY. Foxp3-dependent programme of regulatory T-cell differentiation. Nature. 2007;445:771–5.PubMedCrossRefGoogle Scholar
  148. 148.
    Zheng Y, Josefowicz SZ, Kas A, Chu TT, Gavin MA, Rudensky AY. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature. 2007;445:936–40.PubMedCrossRefGoogle Scholar
  149. 149.
    Hill JA, Feuerer M, Tash K, Haxhinasto S, Perez J, Melamed R, Mathis D, Benoist C. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 2007;27:786–800.PubMedCrossRefGoogle Scholar
  150. 150.
    Zheng Y, Rudensky AY. Foxp3 in control of the regulatory T cell lineage. Nat Immunol. 2007;8:457–62.PubMedCrossRefGoogle Scholar
  151. 151.
    Valencia X, Stephen G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood. 2006;108:253–61.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  1. 1.Lineberger Comprehensive Cancer Center, Department of Microbiology and ImmunologyThe University of North Carolina at Chapel Hill, School of MedicineNorth CarolinaUSA
  2. 2.Department of ImmunobiologyYale University School of MedicineNew HavenUSA
  3. 3.Howard Hughes Medical InstituteNew HavenUSA

Personalised recommendations