Skip to main content
SpringerLink
Log in

TGF-Beta and Regulatory T Cells

  • Chapter
  • First Online:
Regulatory T Cells and Clinical Application

  • 764 Accesses

Abstract

Suppression of the immune system is critical in maintaining self-tolerance and immune homeostasis. Multiple types of cytokines and cell types actively suppress immune responses. Among them, the pleiotropic cytokine TGF-β, and naturally occurring regulatory T cells (Treg) are the best characterized. Dysregulation of either one leads to various immunopathologies under physiological conditions, demonstrating their essential roles in immune suppression. In addition, therapeutic strategies to treat aberrations of immune function by manipulating TGF-β and Treg functions have shown promising results. In this chapter, we will discuss the biologic functions of TGF-β and Treg, and the potential therapeutic effects on immune-related diseases through the manipulation of TGF-β and Treg function.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. R. K. Gershon. A disquisition on suppressor T cells. Transplant Rev, 1975 26, 170–85

    PubMed  CAS  Google Scholar 

  2. G. C. Blobe; W. P. Schiemann; H. F. Lodish. Role of transforming growth factor beta in human disease. N Engl J Med, 2000 May 4, 342, 1350–8

    PubMed  CAS  Google Scholar 

  3. J. H. Kehrl; A. B. Roberts; L. M. Wakefield; S. Jakowlew; M. B. Sporn; A. S. Fauci. Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol, 1986 Dec 15, 137, 3855–60

    PubMed  CAS  Google Scholar 

  4. J. H. Kehrl; L. M. Wakefield; A. B. Roberts; S. Jakowlew; M. Alvarez-Mon; R. Derynck; M. B. Sporn; A. S. Fauci. 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 May 1, 163, 1037–50

    PubMed  CAS  Google Scholar 

  5. A. B. Kulkarni; C. G. Huh; D. Becker; A. Geiser; M. Lyght; K. C. Flanders; A. B. Roberts; M. B. Sporn; J. M. Ward; S. Karlsson. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA, 1993 Jan 15, 90, 770–4

    PubMed  CAS  Google Scholar 

  6. M. M. Shull; I. Ormsby; A. B. Kier; S. Pawlowski; R. J. Diebold; M. Yin; R. Allen; C. Sidman; G. Proetzel; D. Calvin; et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature, 1992 Oct 22, 359, 693–9

    PubMed  CAS  Google Scholar 

  7. B. B. Cazac; J. Roes. TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo. Immunity, 2000 Oct, 13, 443–51

    PubMed  CAS  Google Scholar 

  8. M. B. Datto; J. P. Frederick; L. Pan; A. J. Borton; Y. Zhuang; X. F. Wang. Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol Cell Biol, 1999 Apr, 19, 2495–504

    PubMed  CAS  Google Scholar 

  9. L. Gorelik; R. A. Flavell. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity, 2000 Feb, 12, 171–81

    PubMed  CAS  Google Scholar 

  10. Y. Laouar; F. S. Sutterwala; L. Gorelik; R. A. Flavell. Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. Nat Immunol, 2005 Jun, 6, 600–7

    PubMed  CAS  Google Scholar 

  11. P. J. Lucas; S. J. Kim; S. J. Melby; R. E. Gress. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor beta II receptor. J Exp Med, 2000 Apr 3, 191, 1187–96

    PubMed  CAS  Google Scholar 

  12. A. Nakao; S. Miike; M. Hatano; K. Okumura; T. Tokuhisa; C. Ra; I. Iwamoto. 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 Jul 17, 192, 151–8

    PubMed  CAS  Google Scholar 

  13. X. Yang; J. J. Letterio; R. J. Lechleider; L. Chen; R. Hayman; H. Gu; A. B. Roberts; C. Deng. Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. Embo J, 1999 Mar 1, 18, 1280–91

    PubMed  CAS  Google Scholar 

  14. H. Chang; C. W. Brown; M. M. Matzuk. Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev, 2002 Dec, 23, 787–823

    PubMed  CAS  Google Scholar 

  15. R. Govinden; K. D. Bhoola. Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther, 2003 May, 98, 257–65

    PubMed  CAS  Google Scholar 

  16. C. M. Dubois; M. H. Laprise; F. Blanchette; L. E. Gentry; R. Leduc. Processing of transforming growth factor beta 1 precursor by human furin convertase. J Biol Chem, 1995 May 5, 270, 10618–24

    PubMed  CAS  Google Scholar 

  17. J. P. Annes; Y. Chen; J. S. Munger; D. B. Rifkin. Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1. J Cell Biol, 2004 Jun 7, 165, 723–34

    PubMed  CAS  Google Scholar 

  18. J. P. Annes; J. S. Munger; D. B. Rifkin. Making sense of latent TGFbeta activation. J Cell Sci, 2003 Jan 15, 116, 217–24

    PubMed  CAS  Google Scholar 

  19. S. E. Crawford; V. Stellmach; J. E. Murphy-Ullrich; S. M. Ribeiro; J. Lawler; R. O. Hynes; G. P. Boivin; N. Bouck. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell, 1998 Jun 26, 93, 1159–70

    PubMed  CAS  Google Scholar 

  20. J. S. Munger; X. Huang; H. Kawakatsu; M. J. Griffiths; S. L. Dalton; J. Wu; J. F. Pittet; N. Kaminski; C. Garat; M. A. Matthay; D. B. Rifkin; D. Sheppard. The integrin alpha v beta 6 binds and activates latent TGF beta 1: A mechanism for regulating pulmonary inflammation and fibrosis. Cell, 1999 Feb 5, 96, 319–28

    PubMed  CAS  Google Scholar 

  21. T. Yehualaeshet; R. O'Connor; J. Green-Johnson; S. Mai; R. Silverstein; J. E. Murphy-Ullrich; N. Khalil. 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 Sep, 155, 841–51

    PubMed  CAS  Google Scholar 

  22. J. J. Letterio; A. B. Roberts. Regulation of immune responses by TGF-beta. Annu Rev Immunol, 1998 16, 137–61

    PubMed  CAS  Google Scholar 

  23. E. A. Green; L. Gorelik; C. M. McGregor; E. H. Tran; R. A. Flavell. 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, 2003 Sep 16, 100, 10878–83

    PubMed  CAS  Google Scholar 

  24. J. Massague. TGF-beta signal transduction. Annu Rev Biochem, 1998, 67, 753–91

    PubMed  CAS  Google Scholar 

  25. M. Huse; T. W. Muir; L. Xu; Y. G. Chen; J. Kuriyan; J. Massague. The TGF beta receptor activation process: An inhibitor- to substrate-binding switch. Mol Cell, 2001 Sep, 8, 671–82

    PubMed  CAS  Google Scholar 

  26. G. J. Inman; F. J. Nicolas; C. S. Hill. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Mol Cell, 2002 Aug, 10, 283–94

    PubMed  CAS  Google Scholar 

  27. K. Johnson; H. Kirkpatrick; A. Comer; F. M. Hoffmann; A. Laughon. Interaction of Smad complexes with tripartite DNA-binding sites. J Biol Chem, 1999 Jul 16, 274, 20709–16

    PubMed  CAS  Google Scholar 

  28. Y. Shi; Y. F. Wang; L. Jayaraman; H. Yang; J. Massague; N. P. Pavletich. Crystal structure of a Smad MH1 domain bound to DNA: Insights on DNA binding in TGF-beta signaling. Cell, 1998 Sep 4, 94, 585–94

    PubMed  CAS  Google Scholar 

  29. L. Zawel; J. L. Dai; P. Buckhaults; S. Zhou; K. W. Kinzler; B. Vogelstein; S. E. Kern. Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell, 1998 Mar, 1, 611–7

    PubMed  CAS  Google Scholar 

  30. A. Nakao; M. Afrakhte; A. Moren; T. Nakayama; J. L. Christian; R. Heuchel; S. Itoh; M. Kawabata; N. E. Heldin; C. H. Heldin; P. ten Dijke. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature, 1997 Oct 9, 389, 631–5

    Google Scholar 

  31. T. Ebisawa; M. Fukuchi; G. Murakami; T. Chiba; K. Tanaka; T. Imamura; K. Miyazono. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem, 2001 Apr 20, 276, 12477–80

    PubMed  CAS  Google Scholar 

  32. P. Kavsak; R. K. Rasmussen; C. G. Causing; S. Bonni; H. Zhu; G. H. Thomsen; J. L. Wrana. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell, 2000 Dec, 6, 1365–75

    PubMed  CAS  Google Scholar 

  33. M. E. Engel; M. A. McDonnell; B. K. Law; H. L. Moses. Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J Biol Chem, 1999 Dec 24, 274, 37413–20

    PubMed  CAS  Google Scholar 

  34. L. Yu; M. C. Hebert; Y. E. Zhang. TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. Embo J, 2002 Jul 15, 21, 3749–59

    PubMed  CAS  Google Scholar 

  35. R. Derynck; Y. E. Zhang. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature, 2003 Oct 9, 425, 577–84

    PubMed  CAS  Google Scholar 

  36. F. Blanchette; N. Rivard; P. Rudd; F. Grondin; L. Attisano; C. M. Dubois. 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 Sep 7, 276, 33986–94

    PubMed  CAS  Google Scholar 

  37. M. Funaba; C. M. Zimmerman; L. S. Mathews. Modulation of Smad2-mediated signaling by extracellular signal-regulated kinase. J Biol Chem, 2002 Nov 1, 277, 41361–8

    PubMed  CAS  Google Scholar 

  38. M. Kretzschmar; J. Doody; I. Timokhina; J. Massague. A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev, 1999 Apr 1, 13, 804–16

    PubMed  CAS  Google Scholar 

  39. L. Choy; R. Derynck. 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 Nov 20, 273, 31455–62

    PubMed  CAS  Google Scholar 

  40. I. Griswold-Prenner; C. Kamibayashi; E. M. Maruoka; M. C. Mumby; R. Derynck. 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 Nov, 18, 6595–604

    PubMed  CAS  Google Scholar 

  41. S. McGonigle; M. J. Beall; E. J. Pearce. 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 Jan 15, 41, 579–87

    PubMed  CAS  Google Scholar 

  42. C. H. Chen; C. Seguin-Devaux; N. A. Burke; T. B. Oriss; S. C. Watkins; N. Clipstone; A. Ray. Transforming growth factor beta blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation. J Exp Med, 2003 Jun 16, 197, 1689–99

    PubMed  CAS  Google Scholar 

  43. L. Gorelik; S. Constant; R. A. Flavell. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med, 2002 Jun 3, 195, 1499–505

    PubMed  CAS  Google Scholar 

  44. L. Gorelik; P. E. Fields; R. A. Flavell. Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol, 2000 Nov 1, 165, 4773–7

    PubMed  CAS  Google Scholar 

  45. J. T. Lin; S. L. Martin; L. Xia; J. D. Gorham. 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 May 15, 174, 5950–8

    PubMed  CAS  Google Scholar 

  46. D. A. Thomas; J. Massague. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell, 2005 Nov, 8, 369–80

    PubMed  CAS  Google Scholar 

  47. S. Sakaguchi; N. Sakaguchi; M. Asano; M. Itoh; M. Toda. 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 Aug 1, 155, 1151–64

    PubMed  CAS  Google Scholar 

  48. R. K. Gershon; K. Kondo. Infectious immunological tolerance. Immunology, 1971 Dec, 21, 903–14

    PubMed  CAS  Google Scholar 

  49. R. K. Gershon; K. Kondo. Cell interactions in the induction of tolerance: The role of thymic lymphocytes. Immunology, 1970 May, 18, 723–37

    PubMed  CAS  Google Scholar 

  50. S. Sakaguchi. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol, 2004, 22, 531-62

    PubMed  CAS  Google Scholar 

  51. K. Nakamura; A. Kitani; W. Strober. Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med, 2001 Sep 3, 194, 629–44

    PubMed  CAS  Google Scholar 

  52. S. Sakaguchi. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol, 2005 Apr, 6, 345–52

    PubMed  CAS  Google Scholar 

  53. E. M. Shevach. Regulatory T cells in autoimmmunity∗. Annu Rev Immunol, 2000, 18, 423–49

    PubMed  CAS  Google Scholar 

  54. E. M. Shevach. CD4+ CD25+ suppressor T cells: More questions than answers. Nat Rev Immunol, 2002 Jun, 2, 389–400

    PubMed  CAS  Google Scholar 

  55. J. D. Fontenot; J. L. Dooley; A. G. Farr; A. Y. Rudensky. Developmental regulation of Foxp3 expression during ontogeny. J Exp Med, 2005 Oct 3, 202, 901–6

    PubMed  CAS  Google Scholar 

  56. R. H. Schwartz. Natural regulatory T cells and self-tolerance. Nat Immunol, 2005 Apr, 6, 327–30

    PubMed  CAS  Google Scholar 

  57. C. L. Bennett; J. Christie; F. Ramsdell; M. E. Brunkow; P. J. Ferguson; L. Whitesell; T. E. Kelly; F. T. Saulsbury; P. F. Chance; H. D. Ochs. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet, 2001 Jan, 27, 20–1

    PubMed  CAS  Google Scholar 

  58. M. E. Brunkow; E. W. Jeffery; K. A. Hjerrild; B. Paeper; L. B. Clark; S. A. Yasayko; J. E. Wilkinson; D. Galas; S. F. Ziegler; F. Ramsdell. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet, 2001 Jan, 27, 68–73

    PubMed  CAS  Google Scholar 

  59. S. Hori; T. Nomura; S. Sakaguchi. Control of regulatory T cell development by the transcription factor Foxp3. Science, 2003 Feb 14, 299, 1057–61

    PubMed  CAS  Google Scholar 

  60. R. Khattri; T. Cox; S. A. Yasayko; F. Ramsdell. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol, 2003 Apr, 4, 337–42

    PubMed  CAS  Google Scholar 

  61. R. S. Wildin; F. Ramsdell; J. Peake; F. Faravelli; J. L. Casanova; N. Buist; E. Levy-Lahad; M. Mazzella; O. Goulet; L. Perroni; F. D. Bricarelli; G. Byrne; M. McEuen; S. Proll; M. Appleby; M. E. Brunkow. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet, 2001 Jan, 27, 18–20

    PubMed  CAS  Google Scholar 

  62. X. Chang; J. X. Gao; Q. Jiang; J. Wen; N. Seifers; L. Su; V. L. Godfrey; T. Zuo; P. Zheng; Y. Liu. The Scurfy mutation of FoxP3 in the thymus stroma leads to defective thymopoiesis. J Exp Med, 2005 Oct 17, 202, 1141–51

    PubMed  CAS  Google Scholar 

  63. H. Groux; A. O'Garra; M. Bigler; M. Rouleau; S. Antonenko; J. E. de Vries; M. G. Roncarolo. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature, 1997 Oct 16, 389, 737–42

    Google Scholar 

  64. M. G. Roncarolo; R. Bacchetta; C. Bordignon; S. Narula; M. K. Levings. Type 1 T regulatory cells. Immunol Rev, 2001 Aug, 182, 68–79

    PubMed  CAS  Google Scholar 

  65. P. L. Vieira; J. R. Christensen; S. Minaee; E. J. O'Neill; F. J. Barrat; A. Boonstra; T. Barthlott; B. Stockinger; D. C. Wraith; A. O'Garra. 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 May 15, 172, 5986–93

    PubMed  CAS  Google Scholar 

  66. A. M. Faria; H. L. Weiner. Oral tolerance. Immunol Rev, 2005 Aug, 206, 232–59

    PubMed  CAS  Google Scholar 

  67. H. L. Weiner. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev, 2001 Aug, 182, 207–14

    PubMed  CAS  Google Scholar 

  68. M. Stassen; S. Fondel; T. Bopp; C. Richter; C. Muller; J. Kubach; C. Becker; J. Knop; A. H. Enk; S. Schmitt; E. Schmitt; H. Jonuleit. 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 May, 34, 1303–11

    PubMed  CAS  Google Scholar 

  69. M. O. Li; Y. Y. Wan; S. Sanjabi; A. K. Robertson; R. A. Flavell. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol, 2006, 24, 99–146

    PubMed  CAS  Google Scholar 

  70. T. Brabletz; I. Pfeuffer; E. Schorr; F. Siebelt; T. Wirth; E. Serfling. 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 Feb, 13, 1155–62

    PubMed  CAS  Google Scholar 

  71. S. C. McKarns; R. H. Schwartz; N. E. Kaminski. 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 Apr 1, 172, 4275–84

    PubMed  CAS  Google Scholar 

  72. D. Tzachanis; G. J. Freeman; N. Hirano; A. A. van Puijenbroek; M. W. Delfs; A. Berezovskaya; L. M. Nadler; V. A. Boussiotis. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nat Immunol, 2001 Dec, 2, 1174–82

    Google Scholar 

  73. R. J. Coffey, Jr.; C. C. Bascom; N. J. Sipes; R. Graves-Deal; B. E. Weissman; H. L. Moses. Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta. Mol Cell Biol, 1988 Aug, 8, 3088–93

    PubMed  CAS  Google Scholar 

  74. M. B. Datto; Y. Li; J. F. Panus; D. J. Howe; Y. Xiong; X. F. Wang. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci USA, 1995 Jun 6, 92, 5545–9

    PubMed  CAS  Google Scholar 

  75. G. J. Hannon; D. Beach. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature, 1994 Sep 15, 371, 257–61

    PubMed  CAS  Google Scholar 

  76. K. Polyak; J. Y. Kato; M. J. Solomon; C. J. Sherr; J. Massague; J. M. Roberts; A. Koff. p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev, 1994 Jan, 8, 9–22

    PubMed  CAS  Google Scholar 

  77. J. J. Ruegemer; S. N. Ho; J. A. Augustine; J. W. Schlager; M. P. Bell; D. J. McKean; R. T. Abraham. Regulatory effects of transforming growth factor-beta on IL-2- and IL-4-dependent T cell-cycle progression. J Immunol, 1990 Mar 1, 144, 1767–76

    PubMed  CAS  Google Scholar 

  78. L. A. Wolfraim; T. M. Walz; Z. James; T. Fernandez; J. J. Letterio. 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, 2004 Sep 1, 173, 3093–102

    PubMed  CAS  Google Scholar 

  79. F. Cottrez; H. Groux. Regulation of TGF-beta response during T cell activation is modulated by IL-10. J Immunol, 2001 Jul 15, 167, 773–8

    PubMed  CAS  Google Scholar 

  80. K. M. Murphy; S. L. Reiner. The lineage decisions of helper T cells. Nat Rev Immunol, 2002 Dec, 2, 933–44

    PubMed  CAS  Google Scholar 

  81. T. R. Mosmann; R. L. Coffman. TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol, 1989, 7, 145–73

    PubMed  CAS  Google Scholar 

  82. H. Park; Z. Li; X. O. Yang; S. H. Chang; R. Nurieva; Y. H. Wang; Y. Wang; L. Hood; Z. Zhu; Q. Tian; C. Dong. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol, 2005 Nov, 6, 1133–41

    PubMed  CAS  Google Scholar 

  83. S. C. Liang; X. Y. Tan; D. P. Luxenberg; R. Karim; K. Dunussi-Joannopoulos; M. Collins; L. A. Fouser. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med, 2006 Oct 2, 203, 2271–9

    PubMed  CAS  Google Scholar 

  84. L. Gorelik; R. A. Flavell. Transforming growth factor-beta in T-cell biology. Nat Rev Immunol, 2002 Jan, 2, 46–53

    PubMed  CAS  Google Scholar 

  85. M. O. Li; S. Sanjabi; R. A. Flavell. Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity, 2006 Sep, 25, 455–71

    PubMed  CAS  Google Scholar 

  86. S. Sad; T. R. Mosmann. Single IL-2-secreting precursor CD4 T cell can develop into either Th1 or Th2 cytokine secretion phenotype. J Immunol, 1994 Oct 15, 153, 3514–22

    PubMed  CAS  Google Scholar 

  87. M. Veldhoen; R. J. Hocking; C. J. Atkins; R. M. Locksley; B. Stockinger. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity, 2006 Feb, 24, 179–89

    PubMed  CAS  Google Scholar 

  88. P. R. Mangan; L. E. Harrington; D. B. O'Quinn; W. S. Helms; D. C. Bullard; C. O. Elson; R. D. Hatton; S. M. Wahl; T. R. Schoeb; C. T. Weaver. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature, 2006 May 11, 441, 231–4

    PubMed  CAS  Google Scholar 

  89. M. Veldhoen; R. J. Hocking; R. A. Flavell; B. Stockinger. Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol, 2006 Nov, 7, 1151–6

    PubMed  CAS  Google Scholar 

  90. C. T. Weaver; L. E. Harrington; P. R. Mangan; M. Gavrieli; K. M. Murphy. Th17: An effector CD4 T cell lineage with regulatory T cell ties. Immunity, 2006 Jun, 24, 677–88

    PubMed  CAS  Google Scholar 

  91. J. D. Gorham; M. L. Guler; D. Fenoglio; U. Gubler; K. M. Murphy. Low dose TGF-beta attenuates IL-12 responsiveness in murine Th cells. J Immunol, 1998 Aug 15, 161, 1664–70

    PubMed  CAS  Google Scholar 

  92. V. L. Heath; E. E. Murphy; C. Crain; M. G. Tomlinson; A. O'Garra. TGF-beta1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression. Eur J Immunol, 2000 Sep, 30, 2639–49

    PubMed  CAS  Google Scholar 

  93. B. R. Ludviksson; D. Seegers; A. S. Resnick; W. Strober. The effect of TGF-beta1 on immune responses of naive versus memory CD4+ Th1/Th2 T cells. Eur J Immunol, 2000 Jul, 30, 2101–11

    PubMed  CAS  Google Scholar 

  94. A. Kitani; I. Fuss; K. Nakamura; F. Kumaki; T. Usui; W. Strober. 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 Oct 20, 198, 1179–88

    PubMed  CAS  Google Scholar 

  95. M. Ahmadzadeh; S. A. Rosenberg. TGF-beta1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol, 2005 May 1, 174, 5215–23

    PubMed  CAS  Google Scholar 

  96. H. Bonig; U. Banning; M. Hannen; Y. M. Kim; J. Verheyen; C. Mauz-Korholz; D. Korholz. Transforming growth factor-beta1 suppresses interleukin-15-mediated interferon-gamma production in human T lymphocytes. Scand J Immunol, 1999 Dec, 50, 612–8

    PubMed  CAS  Google Scholar 

  97. G. E. Ranges; I. S. Figari; T. Espevik; M. A. Palladino, Jr. Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. J Exp Med, 1987 Oct 1, 166, 991–8

    PubMed  CAS  Google Scholar 

  98. M. J. Smyth; S. L. Strobl; H. A. Young; J. R. Ortaldo; A. C. Ochoa. 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 May 15, 146, 3289–97

    PubMed  CAS  Google Scholar 

  99. T. R. Mempel; M. J. Pittet; K. Khazaie; W. Weninger; R. Weissleder; H. von Boehmer; U. H. von Andrian. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity, 2006 Jul, 25, 129–41

    Google Scholar 

  100. H. M. Lee; S. Rich. Differential activation of CD8+ T cells by transforming growth factor-beta 1. J Immunol, 1993 Jul 15, 151, 668–77

    PubMed  CAS  Google Scholar 

  101. J. D. Gray; T. Liu; N. Huynh; D. A. Horwitz. Transforming growth factor beta enhances the expression of CD154 (CD40L) and production of tumor necrosis factor alpha by human T lymphocytes. Immunol Lett, 2001 Sep 3, 78, 83–8

    PubMed  CAS  Google Scholar 

  102. E. J. Chung; S. H. Choi; Y. H. Shim; Y. J. Bang; K. C. Hur; C. W. Kim. Transforming growth factor-beta induces apoptosis in activated murine T cells through the activation of caspase 1-like protease. Cell Immunol, 2000 Aug 25, 204, 46–54

    PubMed  CAS  Google Scholar 

  103. H. K. Sillett; S. M. Cruickshank; J. Southgate; L. K. Trejdosiewicz. Transforming growth factor-beta promotes ‘death by neglect' in post-activated human T cells. Immunology, 2001 Mar, 102, 310–6

    PubMed  CAS  Google Scholar 

  104. W. Chen; W. Jin; H. Tian; P. Sicurello; M. Frank; J. M. Orenstein; S. M. Wahl. Requirement for transforming growth factor beta1 in controlling T cell apoptosis. J Exp Med, 2001 Aug 20, 194, 439–53

    PubMed  CAS  Google Scholar 

  105. L. Genestier; S. Kasibhatla; T. Brunner; D. R. Green. 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 Jan 18, 189, 231–9

    PubMed  CAS  Google Scholar 

  106. L. A. Rudner; J. T. Lin; I. K. Park; J. M. Cates; D. A. Dyer; D. M. Franz; M. A. French; E. M. Duncan; H. D. White; J. D. Gorham. Necroinflammatory liver disease in BALB/c background, TGF-beta 1-deficient mice requires CD4+ T cells. J Immunol, 2003 May 1, 170, 4785–92

    PubMed  CAS  Google Scholar 

  107. J. J. Letterio; A. G. Geiser; A. B. Kulkarni; H. Dang; L. Kong; T. Nakabayashi; C. L. Mackall; R. E. Gress; A. B. Roberts. Autoimmunity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expression. J Clin Invest, 1996 Nov 1, 98, 2109–19

    PubMed  CAS  Google Scholar 

  108. P. Leveen; J. Larsson; M. Ehinger; C. M. Cilio; M. Sundler; L. J. Sjostrand; R. Holmdahl; S. Karlsson. Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood, 2002 Jul 15, 100, 560–8

    PubMed  CAS  Google Scholar 

  109. A. M. Thornton; E. M. Shevach. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med, 1998 Jul 20, 188, 287–96

    PubMed  CAS  Google Scholar 

  110. T. Barthlott; H. Moncrieffe; M. Veldhoen; C. J. Atkins; J. Christensen; A. O'Garra; B. Stockinger. 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 Mar, 17, 279–88

    PubMed  CAS  Google Scholar 

  111. M. de la Rosa; S. Rutz; H. Dorninger; A. Scheffold. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur J Immunol, 2004 Sep, 34, 2480–8

    PubMed  CAS  Google Scholar 

  112. J. G. Egen; J. P. Allison. Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity, 2002 Jan, 16, 23–35

    PubMed  CAS  Google Scholar 

  113. J. M. Slavik; J. E. Hutchcroft; B. E. Bierer. CD28/CTLA-4 and CD80/CD86 families: Signaling and function. Immunol Res, 1999 19, 1–24

    PubMed  CAS  Google Scholar 

  114. R. J. Greenwald; G. J. Freeman; A. H. Sharpe. The B7 family revisited. Annu Rev Immunol, 2005 23, 515–48

    PubMed  Google Scholar 

  115. E. Boden; Q. Tang; H. Bour-Jordan; J. A. Bluestone. 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

    PubMed  CAS  Google Scholar 

  116. J. D. Fontenot; J. P. Rasmussen; M. A. Gavin; A. Y. Rudensky. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol, 2005 Nov, 6, 1142–51

    PubMed  CAS  Google Scholar 

  117. L. Fahlen; S. Read; L. Gorelik; S. D. Hurst; R. L. Coffman; R. A. Flavell; F. Powrie. T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med, 2005 Mar 7, 201, 737–46

    PubMed  CAS  Google Scholar 

  118. M. L. Chen; M. J. Pittet; L. Gorelik; R. A. Flavell; R. Weissleder; H. von Boehmer; K. Khazaie. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA, 2005 Jan 11, 102, 419–24

    Google Scholar 

  119. H. H. Uhlig; J. Coombes; C. Mottet; A. Izcue; C. Thompson; A. Fanger; A. Tannapfel; J. D. Fontenot; F. Ramsdell; F. Powrie. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol, 2006 Nov 1, 177, 5852–60

    PubMed  CAS  Google Scholar 

  120. M. Kamanaka; S. T. Kim; Y. Y. Wan; F. S. Sutterwala; M. Lara-Tejero; J. E. Galan; E. Harhaj; R. A. Flavell. Expression of Interleukin-10 in Intestinal Lymphocytes Detected by an Interleukin-10 Reporter Knockin tiger Mouse. Immunity, 2006 Nov 27,

    Google Scholar 

  121. C. Asseman; S. Mauze; M. W. Leach; R. L. Coffman; F. Powrie. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med, 1999 Oct 4, 190, 995–1004

    PubMed  CAS  Google Scholar 

  122. J. D. Gray; M. Hirokawa; D. A. Horwitz. The role of transforming growth factor beta in the generation of suppression: An interaction between CD8+ T and NK cells. J Exp Med, 1994 Nov 1, 180, 1937–42

    PubMed  CAS  Google Scholar 

  123. S. Yamagiwa; J. D. Gray; S. Hashimoto; D. A. Horwitz. A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol, 2001 Jun 15, 166, 7282–9

    PubMed  CAS  Google Scholar 

  124. M. C. Fantini; C. Becker; G. Monteleone; F. Pallone; P. R. Galle; M. F. Neurath. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25– T cells through Foxp3 induction and down-regulation of Smad7. J Immunol, 2004 May 1, 172, 5149–53

    PubMed  CAS  Google Scholar 

  125. Y. Y. Wan; R. A. Flavell. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci USA, 2005 Apr 5, 102, 5126–31

    PubMed  CAS  Google Scholar 

  126. S. Rich; M. Seelig; H. M. Lee; J. Lin. Transforming growth factor beta 1 costimulated growth and regulatory function of staphylococcal enterotoxin B-responsive CD8+ T cells. J Immunol, 1995 Jul 15, 155, 609–18

    PubMed  CAS  Google Scholar 

  127. W. Chen; W. Jin; N. Hardegen; K. J. Lei; L. Li; N. Marinos; G. McGrady; S. M. Wahl. 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 Dec 15, 198, 1875–86

    PubMed  CAS  Google Scholar 

  128. D. A. Horwitz; S. G. Zheng; J. D. Gray. The role of the combination of IL-2 and TGF-beta or IL-10 in the generation and function of CD4+ CD25+ and CD8+ regulatory T cell subsets. J Leukoc Biol, 2003 Oct, 74, 471–8

    PubMed  CAS  Google Scholar 

  129. M. K. Levings; R. Sangregorio; M. G. Roncarolo. 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 Jun 4, 193, 1295–302

    PubMed  CAS  Google Scholar 

  130. P. A. Taylor; C. J. Lees; B. R. Blazar. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood, 2002 May 15, 99, 3493–9

    PubMed  CAS  Google Scholar 

  131. J. D. Fontenot; J. P. Rasmussen; L. M. Williams; J. L. Dooley; A. G. Farr; A. Y. Rudensky. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity, 2005 Mar, 22, 329–41

    PubMed  CAS  Google Scholar 

  132. Y. Peng; Y. Laouar; M. O. Li; E. A. Green; R. A. Flavell. TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci USA, 2004 Mar 30, 101, 4572–7

    PubMed  CAS  Google Scholar 

  133. C. Schramm; M. Protschka; H. H. Kohler; J. Podlech; M. J. Reddehase; P. Schirmacher; P. R. Galle; A. W. Lohse; M. Blessing. Impairment of TGF-beta signaling in T cells increases susceptibility to experimental autoimmune hepatitis in mice. Am J Physiol Gastrointest Liver Physiol, 2003 Mar, 284, G525–35

    PubMed  CAS  Google Scholar 

  134. S. Huber; C. Schramm; H. A. Lehr; A. Mann; S. Schmitt; C. Becker; M. Protschka; P. R. Galle; M. F. Neurath; M. Blessing. Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol, 2004 Dec 1, 173, 6526–31

    PubMed  CAS  Google Scholar 

  135. J. C. Marie; J. J. Letterio; M. Gavin; A. Y. Rudensky. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med, 2005 Apr 4, 201, 1061–7

    PubMed  CAS  Google Scholar 

  136. M. Mamura; W. Lee; T. J. Sullivan; A. Felici; A. L. Sowers; J. P. Allison; J. J. Letterio. CD28 disruption exacerbates inflammation in Tgf-beta1–/– mice: In vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-beta1. Blood, 2004 Jun 15, 103, 4594–601

    PubMed  CAS  Google Scholar 

  137. Y. Zhu; J. A. Richardson; L. F. Parada; J. M. Graff. Smad3 mutant mice develop metastatic colorectal cancer. Cell, 1998 Sep 18, 94, 703–14

    PubMed  CAS  Google Scholar 

  138. H. P. Kim; B. G. Kim; J. Letterio; W. J. Leonard. Smad-dependent cooperative regulation of interleukin 2 receptor alpha chain gene expression by T cell receptor and transforming growth factor-beta. J Biol Chem, 2005 Oct 7, 280, 34042–7

    PubMed  CAS  Google Scholar 

  139. J. L. Coombes; N. J. Robinson; K. J. Maloy; H. H. Uhlig; F. Powrie. Regulatory T cells and intestinal homeostasis. Immunol Rev, 2005 Apr, 204, 184–94

    PubMed  CAS  Google Scholar 

  140. K. J. Maloy; L. R. Antonelli; M. Lefevre; F. Powrie. Cure of innate intestinal immune pathology by CD4+CD25+ regulatory T cells. Immunol Lett, 2005 Mar 15, 97, 189–92

    PubMed  CAS  Google Scholar 

  141. M. C. Fantini; C. Becker; I. Tubbe; A. Nikolaev; H. A. Lehr; P. Galle; M. F. Neurath. Transforming growth factor beta induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut, 2006 May, 55, 671–80

    PubMed  CAS  Google Scholar 

  142. E. A. Green; Y. Choi; R. A. Flavell. Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: Highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity, 2002 Feb, 16, 183–91

    PubMed  CAS  Google Scholar 

  143. H. L. Chang; N. Gillett; I. Figari; A. R. Lopez; M. A. Palladino; R. Derynck. Increased transforming growth factor beta expression inhibits cell proliferation in vitro, yet increases tumorigenicity and tumor growth of Meth A sarcoma cells. Cancer Res, 1993 Sep 15, 53, 4391–8

    PubMed  CAS  Google Scholar 

  144. H. Fakhrai; O. Dorigo; D. L. Shawler; H. Lin; D. Mercola; K. L. Black; I. Royston; R. E. Sobol. Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy. Proc Natl Acad Sci USA, 1996 Apr 2, 93, 2909–14

    PubMed  CAS  Google Scholar 

  145. M. Stander; U. Naumann; L. Dumitrescu; M. Heneka; P. Loschmann; E. Gulbins; J. Dichgans; M. Weller. Decorin gene transfer-mediated suppression of TGF-beta synthesis abrogates experimental malignant glioma growth in vivo. Gene Ther, 1998 Sep, 5, 1187–94

    PubMed  CAS  Google Scholar 

  146. G. Torre-Amione; R. D. Beauchamp; H. Koeppen; B. H. Park; H. Schreiber; H. L. Moses; D. A. Rowley. A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. Proc Natl Acad Sci USA, 1990 Feb, 87, 1486–90

    PubMed  CAS  Google Scholar 

  147. L. A. Ormandy; T. Hillemann; H. Wedemeyer; M. P. Manns; T. F. Greten; F. Korangy. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res, 2005 Mar 15, 65, 2457–64

    PubMed  CAS  Google Scholar 

  148. M. Beyer; M. Kochanek; K. Darabi; A. Popov; M. Jensen; E. Endl; P. A. Knolle; R. K. Thomas; M. von Bergwelt-Baildon; S. Debey; M. Hallek; J. L. Schultze. Reduced frequencies and suppressive function of CD4+ CD25high regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood, 2005 May 24,

    Google Scholar 

  149. H. Nishikawa; T. Kato; I. Tawara; T. Takemitsu; K. Saito; L. Wang; Y. Ikarashi; H. Wakasugi; T. Nakayama; M. Taniguchi; K. Kuribayashi; L. J. Old; H. Shiku. Accelerated chemically induced tumor development mediated by CD4+CD25+ regulatory T cells in wild-type hosts. Proc Natl Acad Sci USA, 2005 Jun 16,

    Google Scholar 

  150. S. Onizuka; I. Tawara; J. Shimizu; S. Sakaguchi; T. Fujita; E. Nakayama. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res, 1999 Jul 1, 59, 3128–33

    PubMed  CAS  Google Scholar 

  151. J. Shimizu; S. Yamazaki; S. Sakaguchi. Induction of tumor immunity by removing CD25+CD4+ T cells: A common basis between tumor immunity and autoimmunity. J Immunol, 1999 Nov 15, 163, 5211–8

    PubMed  CAS  Google Scholar 

  152. R. P. Sutmuller; L. M. van Duivenvoorde; A. van Elsas; T. N. Schumacher; M. E. Wildenberg; J. P. Allison; R. E. Toes; R. Offringa; C. J. Melief. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med, 2001 Sep 17, 194, 823–32

    Google Scholar 

Download references

Acknowledgements

The research performed in our laboratory mentioned in this book chapter is supported by the NIH, American Diabetes Association (ADA) and Howard Hughes Medical Institute. R.A.F. is an investigator of the Howard Hughes Medical Institute. Y.Y.W. is supported by a postdoctoral fellowship from Cancer Research Institute (CRI). We are grateful to S. Wrzesinski for the critical reading of this manuscript and helpful comments. We thank F. Manzo for secretarial assistance.

Author information

Authors and Affiliations

  1. Section of Immunobiology, Yale University School of Medicine; Howard Hughes Medical Institute, 300 Cedar Street, New Haven, Connecticut 06520, USA

    Yisong Y. Wan & Richard A. Flavell

Authors
  1. Yisong Y. Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard A. Flavell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard A. Flavell .

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2008 Springer Science+Business Media, LLC

    About this chapter

    Cite this chapter

    Wan, Y.Y., Flavell, R.A. (2008). TGF-Beta and Regulatory T Cells. In: Jiang, S. (eds) Regulatory T Cells and Clinical Application. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77909-6_6

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation