Skip to main content
SpringerLink
Log in

TGF-β Dependent T-Cell Regulation in Colitis and Colon Cancer

  • Chapter
Book cover Transforming Growth Factor-β in Cancer Therapy, Volume II

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 1546 Accesses

Abstract

Transforming growth factor-β (TGF-β) is a potent growth inhibitor endowed with tumor-suppressing activity. Unfortunately, cancers are often resistant to such growth inhibition. This evasion frequently results from a genetic loss of functional TGF-β signaling components. On the other hand, cancer cells often produce high amounts TGF-β1 by themselves and sometimes respond to it with invasion and metastasis. Much effort is being done to develop therapeutic approaches to modulate TGF-β signaling in cancer cells either to inhibit the TGF-β-induced invasive phenotype or to reestablish its growth-inhibitory activities. However, TGF-β is a pleiotropic cytokine with important functions not only in cancer cells, but also in cells of the tumor environment, especially T cells that may help to fight cancer cells.

The following chapter discusses recent advances in our understanding of TGF-β mediated regulation of T-cell responses and will highlight recent investigations on the role of TGF-β in the induction, maintenance and function of T regulatory cells and the implications of these findings for the antitumor immune response.

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 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature 2001;411: 380–384.

    Article  CAS  PubMed  Google Scholar 

  2. Becker C, Fantini MC, Schramm C, et al. TGF-beta suppresses tumor progression in colon cancer by inhibition of Il-6 trans-signaling. Immunity 2004;21:491–501.

    Article  CAS  PubMed  Google Scholar 

  3. Becker C, Fantini MC, Wirtz S, et al. Il-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle 2005;4:217–220.

    CAS  PubMed  Google Scholar 

  4. Reiss M, Barcellos-Hoff MH. Transforming growth factor-beta in breast cancer. a working hypothesis. Breast Cancer Res Treat 1997;45:81–95.

    Article  CAS  PubMed  Google Scholar 

  5. Baillie R, Coombes RC, Smith J. Multiple forms of TGF-beta 1 in breast tissues. A biologically active form of the small latent complex of TGF-beta 1. Eur J Cancer 1996;32A:1566–1573.

    Article  CAS  PubMed  Google Scholar 

  6. Friedman E, Gold LI, Klimstra D, Zeng ZS, Winawer S, Cohen A. High levels of transforming growth factor beta 1 correlate with disease progression in human colon cancer. Cancer Epidemiol Biomarkers Prev 1995;4:549–554.

    CAS  PubMed  Google Scholar 

  7. Reed JA, McNutt NS, Prieto VG, Albino AP. Expression of transforming growth factor-beta 2 in malignant melanoma correlates with the depth of tumor invasion. Implications for tumor progression. Am J Pathol 1994;145:97–104.

    CAS  PubMed  Google Scholar 

  8. Matsuzaki K, Date M, Furukawa F, et al. Autocrine stimulatory mechanism by transforming growth factor beta in human hepatocellular carcinoma. Cancer Res 2000;60:1394–1402.

    CAS  PubMed  Google Scholar 

  9. Kim SJ, Im YH, Markowitz SD, Bang YJ. Molecular mechanisms of inactivation of TGF-beta receptors during carcinogenesis. Cytokine Growth Factor Rev 2000;11:159–168.

    Article  CAS  PubMed  Google Scholar 

  10. Grady WM, Myeroff LL, Swinler SE, et al. Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res 1999;59:320–324.

    CAS  PubMed  Google Scholar 

  11. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 2001;7:1118–1122.

    Article  CAS  PubMed  Google Scholar 

  12. Hoefer M, Anderer FA. Anti-(transforming growth factor beta) antibodies with predefined specificity inhibit metastasis of highly tumorigenic human xenotransplants in Nu/Nu mice. Cancer Immunol Immunother 1995;41:302–308.

    Article  CAS  PubMed  Google Scholar 

  13. Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992;359:693–699.

    Article  CAS  PubMed  Google Scholar 

  14. Kulkarni AB, Huh CG, Becker D, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 1993;90: 770–774.

    Article  CAS  PubMed  Google Scholar 

  15. 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: 1187–1196.

    Article  CAS  PubMed  Google Scholar 

  16. Gorelik L, Flavell RA. Abrogation of TGF-beta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 2000;12:171–181.

    Article  CAS  PubMed  Google Scholar 

  17. Nakao A, Miike S, Hatano M, et al. 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;192:151–158.

    Article  CAS  PubMed  Google Scholar 

  18. Kehrl JH, Wakefield LM, Roberts AB, et al. 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; 163:1037–1050.

    Article  CAS  PubMed  Google Scholar 

  19. Morris DR, Kuepfer CA, Ellingsworth LR, Ogawa Y, Rabinovitch PS. Transforming growth factor-beta blocks proliferation but not early mitogenic signaling events in T-lymphocytes. Exp Cell Res 1989;185:529–534.

    Article  CAS  PubMed  Google Scholar 

  20. Stoeck M, Miescher S, MacDonald HR, Von Fliedner V. Transforming growth factors beta slow down cell-cycle progression in a murine interleukin-2 dependent T-cell line. J Cell Physiol 1989; 141:65–73.

    Article  CAS  PubMed  Google Scholar 

  21. 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;13:1155–1162.

    CAS  PubMed  Google Scholar 

  22. Appleman LJ, Berezovskaya A, Grass I, Boussiotis VA. Cd28 Costimulation mediates T cell expansion via Il-2-independent and Il-2-dependent regulation of cell cycle progression. J Immunol 2000;164:144–151.

    CAS  PubMed  Google Scholar 

  23. Appleman LJ, van Puijenbroek AA, Shu KM, Nadler LM, Boussiotis VA. Cd28 Costimulation Mediates down-regulation of p27kip 1 and cell cycle progression by activation of the pi3k/pkb signaling pathway in primary human T cells. J Immunol 2002;168:2729–2736.

    CAS  PubMed  Google Scholar 

  24. Nakayama K, Ishida N, Shirane M, et al. Mice lacking P27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 1996;85:707–720.

    Article  CAS  PubMed  Google Scholar 

  25. Wolfraim LA, Walz TM, James Z, Fernandez T, Letterio JJ. P21 cip 1 and P27kip 1 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;173:3093–3102.

    CAS  PubMed  Google Scholar 

  26. Coffey RJ, Jr., Bascom CC, Sipes NJ, Graves-Deal R, Weissman BE, Moses HL. Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta. Mol Cell Biol 1988;8:3088–3093.

    CAS  PubMed  Google Scholar 

  27. 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;153:3514–3522.

    CAS  PubMed  Google Scholar 

  28. Swain SL, Huston G, Tonkonogy S, Weinberg A. Transforming growth factor-beta and Il-4 cause helper T cell precursors to develop into distinct effector helper cells that differ in lymphokine secretion pattern and cell surface phenotype. J Immunol 1991;147:2991–3000.

    CAS  PubMed  Google Scholar 

  29. Hoehn P, Goedert S, Germann T, et al. Opposing effects of TGF-beta 2 on the Th1 cell development of naive Cd4+ T cells isolated from different mouse strains. J Immunol 1995;155:3788–3793.

    CAS  PubMed  Google Scholar 

  30. Gorelik L, Constant S, Flavell RA. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 2002;195:1499–1505.

    Article  CAS  PubMed  Google Scholar 

  31. Ulloa L, Doody J, Massagué J. Inhibition of transforming growth factor-beta/Smad signalling by the interferon-gamma/stat pathway. Nature 1999;397:710–713.

    Article  CAS  PubMed  Google Scholar 

  32. Tau GZ, von der Weid T, Lu B, et al. Interferon gamma signaling alters the function of T helper type 1 cells. J Exp Med 2000;192:977–986.

    Article  CAS  PubMed  Google Scholar 

  33. Heath VL, Murphy EE, Crain C, Tomlinson MG, O’Garra A. TGF-betal down-regulates Th2 development and results in decreased Il-4-induced stat6 activation and gata-3 expression. Eur J Immunol 2000;30:2639–2649.

    Article  CAS  PubMed  Google Scholar 

  34. Gorelik L, Fields PE, Flavell RA. Cutting Edge. TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol 2000;165:4773–4777.

    CAS  PubMed  Google Scholar 

  35. Ludviksson BR, Seegers D, Resnick AS, Strober W. The effect of TGF-betal on immune responses of naive versus memory Cd4+ Th1/Th2 T Cells. Eur J Immunol 2000;30:2101–2111.

    Article  CAS  PubMed  Google Scholar 

  36. 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;166:991–998.

    Article  CAS  PubMed  Google Scholar 

  37. 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;155:1151–1164.

    CAS  PubMed  Google Scholar 

  38. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005;6:345–352.

    Article  CAS  PubMed  Google Scholar 

  39. Thornton AM, Shevach EM. Cd4+Cd25+ Immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998;188:287–296.

    Article  CAS  PubMed  Google Scholar 

  40. Levings MK, Sangregorio R, Roncarolo MG. Human Cd25(+)Cd4(+) T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med 2001;193:1295–1302.

    Article  CAS  PubMed  Google Scholar 

  41. Read S, Mauze S, Asseman C, Bean A, Coffman R, Powrie F. Cd38+ Cd45rb(Low) Cd4+ T Cells. A population of T cells with immune regulatory activities in vitro. Eur J Immunol 1998;28: 3435–3447.

    Article  CAS  PubMed  Google Scholar 

  42. Stephens LA, Mottet C, Mason D, Powrie F. Human Cd4(+)Cd25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur J Immunol 2001;31:1247–1254.

    Article  CAS  PubMed  Google Scholar 

  43. Taams LS, Smith J, Rustin MH, Salmon M, Poulter LW, Akbar AN. Human anergic/suppressive Cd4(+)Cd25(+) T Cells. A highly differentiated and apoptosis-prone population. Eur J Immunol 2001;31:1122–1131.

    Article  CAS  PubMed  Google Scholar 

  44. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. Identification and functional characterization of human Cd4(+)Cd25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 2001;193:1285–1294.

    Article  CAS  PubMed  Google Scholar 

  45. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo isolation and characterization of Cd4(+)Cd25(+) T cells with regulatory properties from human blood. J Exp Med 2001; 193:1303–1310.

    Article  CAS  PubMed  Google Scholar 

  46. Ng WF, Duggan PJ, Ponchel F, et al. Human Cd4(+)Cd25(+) Cells. A naturally occurring population of regulatory T cells. Blood 2001;98:2736–2744.

    Article  CAS  PubMed  Google Scholar 

  47. Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by Cd4(+)Cd25(+) Regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 2001;194:629–644.

    Article  CAS  PubMed  Google Scholar 

  48. Nakamura K, Kitani A, Fuss I, et al. TGF-beta 1 plays an important role in the mechanism of Cd4+Cd25+ regulatory T cell activity in both humans and mice. J Immunol 2004;172:834–842.

    CAS  PubMed  Google Scholar 

  49. Fahlen L, Read S, Gorelik L, et al. T cells that cannot respond to TGF-beta escape control by Cd4(+)Cd25(+) regulatory T cells. J Exp Med 2005;201:737–746.

    Article  CAS  PubMed  Google Scholar 

  50. Bachmaier K, Krawczyk C, Kozieradzki I, et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-B. Nature 2000;403:211–216.

    Article  CAS  PubMed  Google Scholar 

  51. Chiang YJ, Kole HK, Brown K, et al. Cbl-B regulates the Cd28 dependence of T-cell activation. Nature 2000;403:216–220.

    Article  CAS  PubMed  Google Scholar 

  52. Wohlfert EA, Callahan MK, Clark RB. Resistance to Cd4+Cd25+ regulatory T cells and TGF-beta in Cbl-B-/-mice. J Immunol 2004;173:1059–1065.

    CAS  PubMed  Google Scholar 

  53. Piccirillo CA, Letterio JJ, Thornton AM, et al. Cd4(+)Cd25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor betal production and responsiveness. J Exp Med 2002;196:237–246.

    Article  CAS  PubMed  Google Scholar 

  54. Letterio JJ, Geiser AG, Kulkarni AB, Roche NS, Sporn MB, Roberts AB. Maternal rescue of transforming growth factor-beta 1 null mice. Science 1994;264:1936–1938.

    Article  CAS  PubMed  Google Scholar 

  55. Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA. Generation ex vivo of tgf-beta-producing regulatory T cells from Cd4+Cd25-precursors. J Immunol 2002;169:4183–4189.

    CAS  PubMed  Google Scholar 

  56. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999;401:708–712.

    Article  CAS  PubMed  Google Scholar 

  57. 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;180:1937–1942.

    Article  CAS  PubMed  Google Scholar 

  58. Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA. A role for TGF-beta in the generation and expansion of Cd4+Cd25+ regulatory T cells from human peripheral blood. J Immunol 2001;166: 7282–7289.

    CAS  PubMed  Google Scholar 

  59. Rao PE, Petrone AL, Ponath PD. Differentiation and expansion of T cells with regulatory function from human peripheral lymphocytes by stimulation in the presence of TGF-β. J Immunol 2005;174:1446–1455.

    CAS  PubMed  Google Scholar 

  60. Fu S, Zhang N, Yopp AC, et al. TGF-beta induces Foxp3 + T-regulatory cells from Cd4+Cd25-precursors. Am J Transplant 2004;4:1614–1627.

    Article  CAS  PubMed  Google Scholar 

  61. Park HB, Paik DJ, Jang E, Hong S, Youn J. Acquisition of anergic and suppressive activities in transforming growth factor-beta-costimulated Cd4+Cd25-T Cells. Int Immunol 2004;16:1203–1213.

    Article  CAS  PubMed  Google Scholar 

  62. Chen W, Jin W, Hardegen N, et al. 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;198:1875–1886.

    Article  CAS  PubMed  Google Scholar 

  63. 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;172:5149–5153.

    CAS  PubMed  Google Scholar 

  64. Huber S, Schramm C, Lehr HA, et al. 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: 6526–6531.

    CAS  PubMed  Google Scholar 

  65. 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 USA 2004;101:4572–4577.

    Article  CAS  PubMed  Google Scholar 

  66. Cobbold SP, Castejon R, Adams E, et al. Induction of Foxp3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 2004;172:6003–6010.

    CAS  PubMed  Google Scholar 

  67. Marie JC, Letterio JJ, Gavin M, Rudensky AY. TGF-betal maintains suppressor function and Foxp3 expression in Cd4+Cd25+ regulatory T cells. J Exp Med 2005;201:1061–1067.

    Article  CAS  PubMed  Google Scholar 

  68. Schramm C, Huber S, Protschka M, et al. TGF-beta regulates the Cd4+Cd25+ T-cell pool and the expression of Foxp3 in vivo. Int Immunol 2004;16:1241–1249.

    Article  CAS  PubMed  Google Scholar 

  69. Gorczynski RM, Lee L, Boudakov I. Augmented induction of Cd4+Cd25+ Treg using monoclonal antibodies to Cd200r. Transplantation 2005;79:1180–1183.

    Article  CAS  PubMed  Google Scholar 

  70. Luo X, Yang H, Kim IS, et al. Systemic transforming growth factor-betal gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice. Transplantation 2005;79:1091–1096.

    Article  CAS  PubMed  Google Scholar 

  71. Zheng SG, Wang JH, Koss MN, Quismorio F, Jr., Gray JD, Horwitz DA. Cd4+ and Cd8+ regulatory T cells generated ex vivo with Il-2 and TGF-beta suppress a stimulatory graft-versus-host disease with a lupus-like syndrome. J Immunol 2004;172:1531–1539.

    CAS  PubMed  Google Scholar 

  72. Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 1997;389:631–635.

    Article  CAS  PubMed  Google Scholar 

  73. Mizobuchi T, Yasufuku K, Zheng Y, et al. Differential expression of Smad7 transcripts identifies the Cd4+Cd45rc high regulatory T cells that mediate type V collagen-induced tolerance to lung allografts. J Immunol 2003;171:1140–1147.

    CAS  PubMed  Google Scholar 

  74. Zelenay S, Lopes-Carvalho T, Caramalho I, Moraes-Fontes MF, Rebelo M, Demengeot J. Foxp3+Cd25-Cd4 T cells constitute a reservoir of committed regulatory cells that regain Cd25 expression upon homeostatic expansion. Proc Natl Acad Sci USA 2005;102:4091–4096.

    Article  CAS  PubMed  Google Scholar 

  75. Rosendahl A, Speletas M, Leandersson K, Ivars F, Sideras P. Transforming growth factor-beta-and activin-Smad signaling pathways are activated at distinct maturation stages of the thymopoeisis. Int Immunol 2003;15:1401–1414.

    Article  CAS  PubMed  Google Scholar 

  76. Schluesener H, Jung S, Salvetti M. Susceptibility, resistance of human autoimmune T Cell activation to the immunoregulatory effects of transforming growth factor (TGF) beta 1, beta 2, and beta 1.2. J Neuroimmunol 1990;28:271–276.

    Article  CAS  PubMed  Google Scholar 

  77. Wan YY, Flavell RA. Identifying Foxp3-expressing supressor T cells with a bicistronic reporter. Proc Natl Acad Sci USA 2005;102:5126–5131.

    Article  CAS  PubMed  Google Scholar 

  78. Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. 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;194:823–832.

    Article  CAS  PubMed  Google Scholar 

  79. Shimizu J, Yamazaki S, Sakaguchi S. Induction of tumor immunity by removing Cd25+Cd4+T Cells: a common basis between tumor immunity and autoimmunity. J Immunol 1999;5211-5218.

    Google Scholar 

  80. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of Anti-Cd25 (Interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 1999;59:3128–3133.

    CAS  PubMed  Google Scholar 

  81. Jones E, Dahm-Vicker M, Simon AK et al. Depletion of Cd25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2002;2:1.

    PubMed  Google Scholar 

  82. Chen ML, Pittet MJ, Gorelik L, et al. Regulatory T cells suppress tumor-specific Cd8 T Cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA 2005;102:419–424.

    Article  CAS  PubMed  Google Scholar 

  83. Yu P, Lee Y, Liu W, et al. Intratumor depletion of Cd4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med 2005;201:779–791.

    Article  CAS  PubMed  Google Scholar 

  84. Mowat AM. Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol 2003;3:331–341.

    Article  CAS  PubMed  Google Scholar 

  85. Fuss IJ, Boirivant M, Lacy B, Strober W. The interrelated roles of TGF-beta and IL-10 in the regulation of experimental colitis. J Immunol 2002;168:900–908.

    CAS  PubMed  Google Scholar 

  86. Neurath MF, Fuss I, Kelsall BL, Presky DH, Waegell W, Strober W. Experimental granulomatous colitis in mice is abrogated by induction of TGF-Beta-mediated oral tolerance. J Exp Med 1996; 183:2605–2616.

    Article  CAS  PubMed  Google Scholar 

  87. Thorstenson KM, Khoruts A. Generation of anergic and potentially immunoregulatory cd25+cd4 t cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J Immunol 2001;167:188–195.

    CAS  PubMed  Google Scholar 

  88. Zhang X, Izikson L, Liu L, Weiner HL. Activation of Cd25(+)Cd4(+) regulatory T cells by oral antigen administration. J Immunol 2001;167:4245–4253.

    CAS  PubMed  Google Scholar 

  89. Chung Y, Lee SH, Kim DH, Kang CY. Complementary role of Cd4+Cd25+ regulatory T cells and TGF-β in oral tolerance. J Leukoc Biol 2005;77:906–913.

    Article  CAS  PubMed  Google Scholar 

  90. Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille JJ, Curotto de Lafaille MA. Oral tolerance in the absence of naturally occurring tregs. J Clin Invest 2005.

    Google Scholar 

  91. Gonnella PA, Chen Y Inobe J, Komagata Y, Quartulli M, Weiner HL. In situ immune response in gut-associated lymphoid tissue (Galt) following oral antigen in Tcr-transgenic mice. J Immunol 1998;160:4708–4718.

    CAS  PubMed  Google Scholar 

  92. Chen W, Wahl SM, TGF-Beta. The missing link in Cd4+Cd25+ regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev 2003;14:85–89.

    Article  CAS  PubMed  Google Scholar 

  93. Yang X, Letterio JJ, Lechleider RJ, et al. Targeted disruption of Smad3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J 1999;18:1280–1291.

    Article  CAS  PubMed  Google Scholar 

  94. Monteleone G, Kumberova A, Croft NM, McKenzie C, Steer HW, MacDonald TT. Blocking Smad7 restores TGF-betal signaling in chronic inflammatory bowel disease. J Clin Invest 2001; 108:601–609.

    CAS  PubMed  Google Scholar 

  95. Babyatsky MW, Rossiter G, Podolsky DK. Expression of transforming growth factors alpha and beta in colonic mucosa in inflammatory bowel disease. Gastroenterology 1996;110:975–984.

    Article  CAS  PubMed  Google Scholar 

  96. Monteleone G, Del Vecchio Blanco G, Palmieri G, et al. Induction and regulation of Smad7 in the gastric mucosa of patients with helicobacter pylori infection. Gastroenterology 2004;126:674–682.

    Article  CAS  PubMed  Google Scholar 

  97. Makita S, Kanai T, Oshima S, et al. Cd4+Cd25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol 2004;173:3119–3130.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Clinical Immunology, Department of Medicine, The University of Mainz, Mainz, Germany

    Christoph Becker MD, PhD & Markus F. Neurath MD, PhD

Authors
  1. Christoph Becker MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus F. Neurath MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Cancer Training Branch, Office of Centers, Training and Resources, National Cancer Institute, Bethesda, MD

    Sonia B. Jakowlew PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Becker, C., Neurath, M.F. (2008). TGF-β Dependent T-Cell Regulation in Colitis and Colon Cancer. In: Jakowlew, S.B. (eds) Transforming Growth Factor-β in Cancer Therapy, Volume II. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-293-9_11

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-293-9_11

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-715-0

  • Online ISBN: 978-1-59745-293-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation