Transforming Growth Factor-Beta: Recent Advances on Its Role in Immune Tolerance

  • Pierre-Yves MantelEmail author
  • Carsten B. Schmidt-Weber
Part of the Methods in Molecular Biology book series (MIMB, volume 677)


Transforming growth factor (TGF- β1) is a pleiotropic cytokine, secreted by immune and nonhematopoietic cells. TGF-β is involved in many different critical processes, such as embryonal development, cellular maturation and differentiation, wound healing, and immune regulation. It maintains immune homeostasis by acting as a potent immune suppressor through inhibition of proliferation, differentiation, activation, and effector function of immune cells. Paradoxically, depending on the context, it displays proinflammatory properties by being a potent chemoattractant for neutrophils and promoting inflammation. In addition, it does not only induce differentiation into the anti-inflammatory Treg cells, but also into the proinflammatory Th17 and Th9 cells and inhibits Th22 differentiation. TGF-β has been demonstrated to be involved in multiple pathologies. In infections, it protects against collateral damages caused by the immune system, but it also promotes immune evasion and chronic infections. In autoimmune diseases, a TGF-β dysfunction leads to the loss of tolerance to self-antigens. In cancer, TGF-β is a potent inhibitor of cell proliferation and acts as a tumor suppressor at the beginning of tumorogenesis. However, once the cells become resistant to TGF-β, it mainly supports tumor growth and metastasis by promoting immune evasion and angiogenesis. In asthma, it is assumed to promote allergen tolerance, but plays a detrimental role in irreversible remodeling of the airways. Despite the high numbers of TGF-β-targeted pathways, it is a promising drug target for treatment of autoimmunity, cancer, fibrosis, if cell specificity can be achieved.

This review summarizes the progresses that have been accomplished on the understanding of TGF-β’s signaling in the immune homeostasis and its role in pathogenesis.

Key words

TGF-β SMAD Immune regulation Tolerance Immunopatholgy T cell differentiation Th17 Th22 Th9 T regulatory cells FOXP3 RORγt 


  1. 1.
    de Larco, J. and Todaro, G. (1978) Growth factors from murine sarcoma virus-transformed cells. Proc Natl Acad Sci U S A 75, 4001–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Roberts, A., Frolik, C., Anzano, M., and Sporn, M. (1983) Transforming growth factors from neoplastic and nonneoplastic tissues. Fed Proc 42, 2621–6.PubMedGoogle Scholar
  3. 3.
    Chang, H., Brown, C., and Matzuk, M. (2002) Genetic analysis of the mammalian transforming growth factor-beta superfamily. Endocr Rev 23, 787–823.PubMedCrossRefGoogle Scholar
  4. 4.
    Massague, J. (2000) How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1, 169–78.PubMedCrossRefGoogle Scholar
  5. 5.
    Govinden, R. and Bhoola, K. (2003) Genea logy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther 98, 257–65.PubMedCrossRefGoogle Scholar
  6. 6.
    Kaartinen, V., Voncken, J., Shuler, C., Warburton, D., Bu, D., Heisterkamp, N., and Groffen, J. (1995) Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat Genet 11, 415–21.PubMedCrossRefGoogle Scholar
  7. 7.
    Proetzel, G., Pawlowski, S., Wiles, M., Yin, M., Boivin, G., Howles, P., Ding, J., Ferguson, M., and Doetschman, T. (1995) Transforming growth factor-beta 3 is required for secondary palate fusion. Nat Genet 11, 409–14.PubMedCrossRefGoogle Scholar
  8. 8.
    Sanford, L., Ormsby, I., Gittenberger-de Groot, A., Sariola, H., Friedman, R., Boivin, G., Cardell, E., and Doetschman, T. (1997) TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 124, 2659–70.PubMedGoogle Scholar
  9. 9.
    Shull, M., Ormsby, I., Kier, A., Pawlowski, S., Diebold, R., Yin, M., Allen, R., Sidman, C., Proetzel, G., Calvin, D., et al. (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359, 693–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Matusevicius, D., Kivisakk, P., He, B., Kostulas, N., Ozenci, V., Fredrikson, S., and Link, H. (1999) Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler 5, 101–4.PubMedGoogle Scholar
  11. 11.
    Annes, J., Chen, Y., Munger, J., and Rifkin, D. (2004) Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1. J Cell Biol 165, 723–34.PubMedCrossRefGoogle Scholar
  12. 12.
    Crawford, S., Stellmach, V., Murphy-Ullrich, J., Ribeiro, S., Lawler, J., Hynes, R., Boivin, G., and Bouck, N. (1998) Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 93, 1159–70.PubMedCrossRefGoogle Scholar
  13. 13.
    Munger, J., Huang, X., Kawakatsu, H., Griffiths, M., Dalton, S., Wu, J., Pittet, J., Kaminski, N., Garat, C., Matthay, M., Rifkin, D., and Sheppard, D. (1999) The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–28.PubMedCrossRefGoogle Scholar
  14. 14.
    Nunes, I., Shapiro, R., and Rifkin, D. (1995) Characterization of latent TGF-beta activation by murine peritoneal macrophages. J Immunol 155, 1450–9.PubMedGoogle Scholar
  15. 15.
    Schmidt-Weber, C. B., Letarte, M., Kunzmann, S., Ruckert, B., Bernabeu, C., and Blaser, K. (2005) TGF-{beta} signaling of human T cells is modulated by the ancillary TGF-{beta} receptor endoglin. Int Immunol 17, 921–30.PubMedCrossRefGoogle Scholar
  16. 16.
    Graff, J., Bansal, A., and Melton, D. (1996) Xenopus Mad proteins transduce distinct subsets of signals for the TGF beta superfamily. Cell 85, 479–87.PubMedCrossRefGoogle Scholar
  17. 17.
    Zhang, Y., Feng, X., We, R., and Derynck, R. (1996) Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature 383, 168–72.PubMedCrossRefGoogle Scholar
  18. 18.
    Tsukazaki, T., Chiang, T., Davison, A., Attisano, L., and Wrana, J. (1998) SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor. Cell 95, 779–91.PubMedCrossRefGoogle Scholar
  19. 19.
    Kunzmann, S., Wohlfahrt, J. G., Itoh, S., Asao, H., Komada, M., Akdis, C. A., Blaser, K., and Schmidt-Weber, C. B. (2003) SARA and Hgs attenuate susceptibility to TGF-beta1-mediated T cell suppression. FASEB J 17, 194–202.PubMedCrossRefGoogle Scholar
  20. 20.
    Tajima, Y., Goto, K., Yoshida, M., Shinomiya, K., Sekimoto, T., Yoneda, Y., Miyazono, K., and Imamura, T. (2003) Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-beta signaling by Smad7. J Biol Chem 278, 10716–21.PubMedCrossRefGoogle Scholar
  21. 21.
    Zawel, L., Dai, J., Buckhaults, P., Zhou, S., Kinzler, K., Vogelstein, B., and Kern, S. (1998) Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1, 611–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Lo, R. and Massague, J. (1999) Ubiquitin-dependent degradation of TGF-beta-activated smad2. Nat Cell Biol 1, 472–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Lin, X., Liang, M., Liang, Y., Brunicardi, F., Melchior, F., and Feng, X. (2003) Activation of transforming growth factor-beta signaling by SUMO-1 modification of tumor suppressor Smad4/DPC4. J Biol Chem 278, 18714–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Gronroos, E., Hellman, U., Heldin, C., and Ericsson, J. (2002) Control of Smad7 stability by competition between acetylation and ubiquitination. Mol Cell 10, 483–93.PubMedCrossRefGoogle Scholar
  25. 25.
    Kehrl, J., Wakefield, L., Roberts, A., Jakowlew, S., Alvarez-Mon, M., Derynck, R., Sporn, M., and Fauci, A. (1986) Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med 163, 1037–50.PubMedCrossRefGoogle Scholar
  26. 26.
    Kulkarni, A., Huh, C., Becker, D., Geiser, A., Lyght, M., Flanders, K., Roberts, A., Sporn, M., Ward, J., and Karlsson, S. (1993) Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci U S A 90, 770–4.PubMedCrossRefGoogle Scholar
  27. 27.
    Letterio, J., Geiser, A., Kulkarni, A., Dang, H., Kong, L., Nakabayashi, T., Mackall, C., Gress, R., and Roberts, A. (1996) Autoi mmu nity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expression. J Clin Invest 98, 2109–19.PubMedCrossRefGoogle Scholar
  28. 28.
    Gorelik, L. and Flavell, R. (2000) Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12, 171–81.PubMedCrossRefGoogle Scholar
  29. 29.
    Marie, J., Liggitt, D., and Rudensky, A. (2006) Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25, 441–54.PubMedCrossRefGoogle Scholar
  30. 30.
    Waldrip, W., Bikoff, E., Hoodless, P., Wrana, J., and Robertson, E. (1998) Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell 92, 797–808.PubMedCrossRefGoogle Scholar
  31. 31.
    Chang, H., Huylebroeck, D., Verschueren, K., Guo, Q., Matzuk, M., and Zwijsen, A. (1999) Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development 126, 1631–42.PubMedGoogle Scholar
  32. 32.
    Yang, X., Letterio, J., Lechleider, R., Chen, L., Hayman, R., Gu, H., Roberts, A., and Deng, C. (1999) Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta. EMBO J 18, 1280–91.PubMedCrossRefGoogle Scholar
  33. 33.
    Nakao, A., Miike, S., Hatano, M., Okumura, K., Tokuhisa, T., Ra, C., and Iwamoto, I. (2000) 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 192, 151–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Gorelik, L., Fields, P., and Flavell, R. (2000) Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol 165, 4773–7.PubMedGoogle Scholar
  35. 35.
    Heath, V. L., Murphy, E. E., Crain, C., Tomlinson, M. G., and O’Garra, A. (2000) TGF-beta1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression. Eur J Immunol 30, 2639–49.PubMedCrossRefGoogle Scholar
  36. 36.
    Mantel, P., Kuipers, H., Boyman, O., Rhyner, C., Ouaked, N., Ruckert, B., Karagiannidis, C., Lambrecht, B., Hendriks, R., Crameri, R., Akdis, C., Blaser, K., and Schmidt-Weber, C. (2007) GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol 5, e329.PubMedCrossRefGoogle Scholar
  37. 37.
    Gorelik, L., Constant, S., and Flavell, R. (2002) Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 195, 1499–505.PubMedCrossRefGoogle Scholar
  38. 38.
    Gorham, J., Guler, M., Fenoglio, D., Gubler, U., and Murphy, K. (1998) Low dose TGF-beta attenuates IL-12 responsiveness in murine Th cells. J Immunol 161, 1664–70.PubMedGoogle Scholar
  39. 39.
    Chen, W., Jin, W., Hardegen, N., Lei, K., Li, L., Marinos, N., McGrady, G., and Wahl, S. (2003) Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198, 1875–86.PubMedCrossRefGoogle Scholar
  40. 40.
    Gorelik, L., and Flavell, R. (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7, 1118–22.PubMedCrossRefGoogle Scholar
  41. 41.
    Hori, S., Nomura, T., and Sakaguchi, S. (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–61.PubMedCrossRefGoogle Scholar
  42. 42.
    Dardalhon, V., Awasthi, A., Kwon, H., Galileos, G., Gao, W., Sobel, R., Mitsdoerffer, M., Strom, T., Elyaman, W., Ho, I., Khoury, S., Oukka, M., and Kuchroo, V. (2008) IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(−) effector T cells. Nat Immunol 9, 1347–55.PubMedCrossRefGoogle Scholar
  43. 43.
    Veldhoen, M., Hocking, R., Atkins, C., Locksley, R., and Stockinger, B. (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–89.PubMedCrossRefGoogle Scholar
  44. 44.
    Veldhoen, M., Uyttenhove, C., van Snick, J., Helmby, H., Westendorf, A., Buer, J., Martin, B., Wilhelm, C., and Stockinger, B. (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9, 1341–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Gershon, R. K. and Kondo, K. (1970) Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 18, 723–37.PubMedGoogle Scholar
  46. 46.
    Gershon, R. K. and Kondo, K. (1971) Infec tious immunological tolerance. Immunology 21, 903–14.PubMedGoogle Scholar
  47. 47.
    Brunkow, M. E., Jeffery, E. W., Hjerrild, K. A., Paeper, B., Clark, L. B., Yasayko, S. A., Wilkinson, J. E., Galas, D., Ziegler, S. F., and Ramsdell, F. (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27, 68–73.PubMedCrossRefGoogle Scholar
  48. 48.
    Fontenot, J., Dooley, J., Farr, A., and Rudensky, A. (2005) Developmental regulation of Foxp3 expression during ontogeny. J Exp Med 202, 901–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Curotto de Lafaille, M. A., Lino, A. C., Kutchukhidze, N., and Lafaille, J. J. (2004) CD25− T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J Immunol 173, 7259–68.PubMedGoogle Scholar
  50. 50.
    Mucida, D., Kutchukhidze, N., Erazo, A., Russo, M., Lafaille, J. J., and Curotto de Lafaille, M. A. (2005) Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest 115, 1923–33.PubMedCrossRefGoogle Scholar
  51. 51.
    Marie, J., Letterio, J., Gavin, M., and Rudensky, A. (2005) TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 201, 1061–7.PubMedCrossRefGoogle Scholar
  52. 52.
    Fantini, M. C., Becker, C., Monteleone, G., Pallone, F., Galle, P. R., and Neurath, M. F. (2004) Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172, 5149–53.PubMedGoogle Scholar
  53. 53.
    Rao, P. E., Petrone, A. L., and Ponath, P. D. (2005) Differentiation and expansion of T cells with regulatory function from human peripheral lymphocytes by stimulation in the presence of TGF-{beta}. J Immunol 174, 1446–55.PubMedGoogle Scholar
  54. 54.
    Wan, Y. and Flavell, R. (2005) Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci U S A 102, 5126–31.PubMedCrossRefGoogle Scholar
  55. 55.
    Liang, S., Alard, P., Zhao, Y., Parnell, S., Clark, S., and Kosiewicz, M. (2005) Conversion of CD4+ CD25− cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J Exp Med 201, 127–37.PubMedCrossRefGoogle Scholar
  56. 56.
    Apostolou, I., Verginis, P., Kretschmer, K., Polansky, J., Huhn, J., and von Boehmer, H. (2008) Peripherally induced Treg: mode, stability, and role in specific tolerance. J Clin Immunol 28, 619–24.PubMedCrossRefGoogle Scholar
  57. 57.
    Liu, Y., Zhang, P., Li, J., Kulkarni, A., Perruche, S., and Chen, W. (2008) A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol 9, 632–40.PubMedCrossRefGoogle Scholar
  58. 58.
    Cobbold, S., Castejon, R., Adams, E., Zelenika, D., Graca, L., Humm, S., and Waldmann, H. (2004) Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 172, 6003–10.PubMedGoogle Scholar
  59. 59.
    Luo, X., Yang, H., Kim, I., Saint-Hilaire, F., Thomas, D., De, B., Ozkaynak, E., Muthukumar, T., Hancock, W., Crystal, R., and Suthanthiran, M. (2005) Systemic transforming growth factor-beta1 gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice. Transplantation 79, 1091–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Perruche, S., Zhang, P., Liu, Y., Saas, P., Bluestone, J., and Chen, W. (2008) CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells. Nat Med 14, 528–35.PubMedCrossRefGoogle Scholar
  61. 61.
    Kretschmer, K., Apostolou, I., Hawiger, D., Khazaie, K., Nussenzweig, M. C., and von Boehmer, H. (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6, 1219–27.PubMedCrossRefGoogle Scholar
  62. 62.
    Knoechel, B., Lohr, J., Kahn, E., Bluestone, J., and Abbas, A. (2005) Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med 202, 1375–86.PubMedCrossRefGoogle Scholar
  63. 63.
    Belkaid, Y. and Oldenhove, G. (2008) Tuning microenvironments: induction of regulatory T cells by dendritic cells. Immunity 29, 362–71.PubMedCrossRefGoogle Scholar
  64. 64.
    Denning, T., Wang, Y., Patel, S., Williams, I., and Pulendran, B. (2007) Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 8, 1086–94.PubMedCrossRefGoogle Scholar
  65. 65.
    Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., and Cheroutre, H. (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–60.PubMedCrossRefGoogle Scholar
  66. 66.
    Peng, Y., Laouar, Y., Li, M. O., Green, E. A., and Flavell, R. A. (2004) 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 101, 4572–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Kim, H. and Leonard, W. (2007) CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 204, 1543–51.PubMedGoogle Scholar
  68. 68.
    Mantel, P., Ouaked, N., Ruckert, B., Karagiannidis, C., Welz, R., Blaser, K., and Schmidt-Weber, C. (2006) Molecular mechanisms underlying FOXP3 induction in human T cells. J Immunol 176, 3593–602.PubMedGoogle Scholar
  69. 69.
    Hijnen, D., Haeck, I., van Kraats, A. A., Nijhuis, E., de Bruin-Weller, M. S., Bruijnzeel-Koomen, C. A., and Knol, E. F. (2009) Cyclosporin A reduces CD4(+)CD25(+) regulatory T-cell numbers in patients with atopic dermatitis. J Allergy Clin Immunol 124, 856–8.PubMedCrossRefGoogle Scholar
  70. 70.
    Wang, H., Zhao, L., Sun, Z., Sun, L., Zhang, B., and Zhao, Y. (2006) A potential side effect of cyclosporin A: inhibition of CD4(+)CD25(+) regulatory T cells in mice. Transplantation 82, 1484–92.PubMedCrossRefGoogle Scholar
  71. 71.
    Battaglia, M., Stabilini, A., and Roncarolo, M. G. (2005) Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105, 4743–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Korczak-Kowalska, G., Wierzbicki, P., Bocian, K., Klosowska, D., Niemczyk, M., Wyzgal, J., Korecka, A., Durlik, M., Chmura, A., Paczek, L., and Gorski, A. (2007) The influence of immuosuppressive therapy on the development of CD4+CD25+ T cells after renal transplantation. Transplant Proc 39, 2721–3.PubMedCrossRefGoogle Scholar
  73. 73.
    San Segundo, D., Fabrega, E., Lopez-Hoyos, M., and Pons, F. (2007) Reduced numbers of blood natural regulatory T cells in stable liver transplant recipients with high levels of calcineurin inhibitors. Transplant Proc 39, 2290–2.PubMedCrossRefGoogle Scholar
  74. 74.
    Zeiser, R., Nguyen, V., Beilhack, A., Buess, M., Schulz, S., Baker, J., Contag, C., and Negrin, R. (2006) Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 108, 390–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Sauer, S., Bruno, L., Hertweck, A., Finlay, D., Leleu, M., Spivakov, M., Knight, Z., Cobb, B., Cantrell, D., O’Connor, E., Shokat, K., Fisher, A., and Merkenschlager, M. (2008) T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A 105, 7797–802.PubMedCrossRefGoogle Scholar
  76. 76.
    Tai, X., Cowan, M., Feigenbaum, L., and Singer, A. (2005) CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol 6, 152–62.PubMedCrossRefGoogle Scholar
  77. 77.
    Perry, W., Hustad, C., Swing, D., O’Sullivan, T., Jenkins, N., and Copeland, N. (1998) The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a18H mice. Nat Genet 18, 143–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Fang, D., Elly, C., Gao, B., Fang, N., Altman, Y., Joazeiro, C., Hunter, T., Copeland, N., Jenkins, N., and Liu, Y. (2002) Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol 3, 281–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Wohlfert, E., Gorelik, L., Mittler, R., Flavell, R., and Clark, R. (2006) Cutting edge: deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity in vitro and in vivo. J Immunol 176, 1316–20.PubMedGoogle Scholar
  80. 80.
    Tone, Y., Furuuchi, K., Kojima, Y., Tykocinski, M., Greene, M., and Tone, M. (2008) Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol 9, 194–202.PubMedCrossRefGoogle Scholar
  81. 81.
    Samon, J. B., Champhekar, A., Minter, L. M., Telfer, J. C., Miele, L., Fauq, A., Das, P., Golde, T. E., and Osborne, B. A. (2008) Notch1 and TGFbeta1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells. Blood 112, 1813–21.PubMedCrossRefGoogle Scholar
  82. 82.
    Wei, J., Duramad, O., Perng, O., Reiner, S., Liu, Y., and Qin, F. (2007) Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 104, 18169–74.PubMedCrossRefGoogle Scholar
  83. 83.
    Karagiannidis, C., Akdis, M., Holopainen, P., Woolley, N. J., Hense, G., Ruckert, B., Mantel, P. Y., Menz, G., Akdis, C. A., Blaser, K., and Schmidt-Weber, C. B. (2004) Glu cocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol 114, 1425–33.PubMedCrossRefGoogle Scholar
  84. 84.
    Zheng, S. G., Wang, J. H., Stohl, W., Kim, K. S., Gray, J. D., and Horwitz, D. A. (2006) TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176, 3321–9.PubMedGoogle Scholar
  85. 85.
    Polanczyk, M. J., Carson, B. D., Subramanian, S., Afentoulis, M., Vandenbark, A. A., Ziegler, S. F., and Offner, H. (2004) Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol 173, 2227–30.PubMedGoogle Scholar
  86. 86.
    Bour-Jordan, H., Grogan, J., Tang, Q., Auger, J., Locksley, R., and Bluestone, J. (2003) CTLA-4 regulates the requirement for cytokine-induced signals in T(H)2 lineage commitment. Nat Immunol 4, 182–8.PubMedCrossRefGoogle Scholar
  87. 87.
    Quan, A., McCall, M. N., and Sewell, W. A. (2001) Dexamethasone inhibits the binding of nuclear factors to the IL-5 promoter in human CD4 T cells. J Allergy Clin Immunol 108, 340–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Lambert, K. C., Curran, E. M., Judy, B. M., Milligan, G. N., Lubahn, D. B., and Estes, D. M. (2005) Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. J Immunol 175, 5716–23.PubMedGoogle Scholar
  89. 89.
    Nasta, F., Ubaldi, V., Pace, L., Doria, G., and Pioli, C. (2006) Cytotoxic T-lymphocyte antigen-4 inhibits GATA-3 but not T-bet mRNA expression during T helper cell differentiation. Immunology 117, 358–67.PubMedCrossRefGoogle Scholar
  90. 90.
    Ouaked, N., Mantel, P. Y., Bassin, C., Burgler, S., Siegmund, K., Akdis, C. A., and Schmidt-Weber, C. B. (2009) Regulation of the foxp3 gene by the Th1 cytokines: the role of IL-27-induced STAT1. J Immunol 182, 1041–9.PubMedGoogle Scholar
  91. 91.
    Klunker, S., Chong, M. M., Mantel, P. Y., Palomares, O., Bassin, C., Ziegler, M., Ruckert, B., Meiler, F., Akdis, M., Littman, D. R., and Akdis, C. A. (2009) Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells. J Exp Med 206, 2701–15.PubMedCrossRefGoogle Scholar
  92. 92.
    Floess, S., Freyer, J., Siewert, C., Baron, U., Olek, S., Polansky, J., Schlawe, K., Chang, H. D., Bopp, T., Schmitt, E., Klein-Hessling, S., Serfling, E., Hamann, A., and Huehn, J. (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5, e38.PubMedCrossRefGoogle Scholar
  93. 93.
    Zorn, E., Nelson, E. A., Mohseni, M., Porcheray, F., Kim, H., Litsa, D., Bellucci, R., Raderschall, E., Canning, C., Soiffer, R. J., Frank, D. A., and Ritz, J. (2006) IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108, 1571–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Zheng, Y., Josefowicz, S., Chaudhry, A., Peng, X. P., Forbush, K., and Rudensky, A. Y. (2010) Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808–12.PubMedCrossRefGoogle Scholar
  95. 95.
    Korn, T., Bettelli, E., Gao, W., Awasthi, A., Jager, A., Strom, T., Oukka, M., and Kuchroo, V. (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448, 484–7.PubMedCrossRefGoogle Scholar
  96. 96.
    Yang, L., Anderson, D., Baecher-Allan, C., Hastings, W., Bettelli, E., Oukka, M., Kuchroo, V., and Hafler, D. (2008) IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454, 350–2.PubMedCrossRefGoogle Scholar
  97. 97.
    Ivanov, I., McKenzie, B., Zhou, L., Tadokoro, C., Lepelley, A., Lafaille, J., Cua, D., and Littman, D. (2006) The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–33.PubMedCrossRefGoogle Scholar
  98. 98.
    Laurence, A., Tato, C., Davidson, T., Kanno, Y., Chen, Z., Yao, Z., Blank, R., Meylan, F., Siegel, R., Hennighausen, L., Shevach, E., and O’shea, J. (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–81.PubMedCrossRefGoogle Scholar
  99. 99.
    Morishima, N., Mizoguchi, I., Takeda, K., Mizuguchi, J., and Yoshimoto, T. (2009) TGF-beta is necessary for induction of IL-23R and Th17 differentiation by IL-6 and IL-23. Biochem Biophys Res Commun 386, 105–10.PubMedCrossRefGoogle Scholar
  100. 100.
    Manel, N., Unutmaz, D., and Littman, D. (2008) The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORγt. Nat Immunol 9, 641–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T., Oukka, M., Weiner, H., and Kuchroo, V. (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–8.PubMedCrossRefGoogle Scholar
  102. 102.
    Mangan, P., Harrington, L., O’Quinn, D., Helms, W., Bullard, D., Elson, C., Hatton, R., Wahl, S., Schoeb, T., and Weaver, C. (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441, 231–4.PubMedCrossRefGoogle Scholar
  103. 103.
    Batten, M., Li, J., Yi, S., Kljavin, N., Danilenko, D., Lucas, S., Lee, J., de Sauvage, F., and Ghilardi, N. (2006) Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol 7, 929–36.PubMedCrossRefGoogle Scholar
  104. 104.
    Harrington, L., Hatton, R., Mangan, P., Turner, H., Murphy, T., Murphy, K., and Weaver, C. (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6, 1123–32.PubMedCrossRefGoogle Scholar
  105. 105.
    Park, H., Li, Z., Yang, X., Chang, S., Nurieva, R., Wang, Y., Wang, Y., Hood, L., Zhu, Z., Tian, Q., and Dong, C. (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6, 1133–41.PubMedCrossRefGoogle Scholar
  106. 106.
    Stumhofer, J., Laurence, A., Wilson, E., Huang, E., Tato, C., Johnson, L., Villarino, A., Huang, Q., Yoshimura, A., Sehy, D., Saris, C., O’Shea, J., Hennighausen, L., Ernst, M., and Hunter, C. (2006) Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 7, 937–45.PubMedCrossRefGoogle Scholar
  107. 107.
    Pestka, S., Krause, C., Sarkar, D., Walter, M., Shi, Y., and Fisher, P. (2004) Interleukin-10 and related cytokines and receptors. Annu Rev Immunol 22, 929–79.PubMedCrossRefGoogle Scholar
  108. 108.
    Zheng, Y., Valdez, P., Danilenko, D., Hu, Y., Sa, S., Gong, Q., Abbas, A., Modrusan, Z., Ghilardi, N., de Sauvage, F., and Ouyang, W. (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14, 282–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Zheng, Y., Danilenko, D., Valdez, P., Kasman, I., Eastham-Anderson, J., Wu, J., and Ouyang, W. (2007) Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–51.PubMedCrossRefGoogle Scholar
  110. 110.
    Eyerich, S., Eyerich, K., Pennino, D., Carbone, T., Nasorri, F., Pallotta, S., Cianfarani, F., Odorisio, T., Traidl-Hoffmann, C., Behrendt, H., Durham, S. R., Schmidt-Weber, C. B., and Cavani, A. (2009) Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 119, 3573–85.PubMedGoogle Scholar
  111. 111.
    Trifari, S., Kaplan, C., Tran, E., Crellin, N., and Spits, H. (2009) Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol 10, 864–71.PubMedCrossRefGoogle Scholar
  112. 112.
    Vivier, E., Spits, H., and Cupedo, T. (2009) Interleukin-22-producing innate immune cells: new players in mucosal immunity and tissue repair? Nat Rev Immunol 9, 229–34.PubMedCrossRefGoogle Scholar
  113. 113.
    Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A., and Sallusto, F. (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 10, 857–63.PubMedCrossRefGoogle Scholar
  114. 114.
    Kobayashi, S., Yoshida, K., Ward, J., Letterio, J., Longenecker, G., Yaswen, L., Mittleman, B., Mozes, E., Roberts, A., Karlsson, S., and Kulkarni, A. (1999) Beta 2-microglobulin-deficient background ameliorates lethal phenotype of the TGF-beta 1 null mouse. J Immunol 163, 4013–9.PubMedGoogle Scholar
  115. 115.
    Ranges, G., Figari, I., Espevik, T., and Palladino, M. J. (1987) Inhibition of cytotoxic T cell development by transforming growth factor beta and reversal by recombinant tumor necrosis factor alpha. J Exp Med 166, 991–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Smyth, M., Strobl, S., Young, H., Ortaldo, J., and Ochoa, A. (1991) 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 146, 3289–97.PubMedGoogle Scholar
  117. 117.
    Ahmadzadeh, M. and Rosenberg, S. (2005) TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J Immunol 174, 5215–23.PubMedGoogle Scholar
  118. 118.
    Siegmund, K., Ruckert, B., Ouaked, N., Burgler, S., Speiser, A., Akdis, C., and Schmidt-Weber, C. (2009) Unique phenotype of human tonsillar and in vitro-induced FOXP3+CD8+ T cells. J Immunol 182, 2124–30.PubMedCrossRefGoogle Scholar
  119. 119.
    Cazac, B. and Roes, J. (2000) TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo. Immunity 13, 443–51.PubMedCrossRefGoogle Scholar
  120. 120.
    van Vlasselaer, P., Punnonen, J., and de Vries, J. (1992) Transforming growth factor-beta directs IgA switching in human B cells. J Immunol 148, 2062–7.PubMedGoogle Scholar
  121. 121.
    Kee, B., Rivera, R., and Murre, C. (2001) Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-beta. Nat Immunol 2, 242–7.PubMedCrossRefGoogle Scholar
  122. 122.
    Petit-Koskas, E., Genot, E., Lawrence, D., and Kolb, J. (1988) Inhibition of the proliferative response of human B lymphocytes to B cell growth factor by transforming growth factor-beta. Eur J Immunol 18, 111–6.PubMedCrossRefGoogle Scholar
  123. 123.
    Arsura, M., Wu, M., and Sonenshein, G. (1996) TGF beta 1 inhibits NF-kappa B/Rel activity inducing apoptosis of B cells: transcriptional activation of I kappa B alpha. Immunity 5, 31–40.PubMedCrossRefGoogle Scholar
  124. 124.
    Biron, C., Nguyen, K., Pien, G., Cousens, L., and Salazar-Mather, T. (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17, 189–220.PubMedCrossRefGoogle Scholar
  125. 125.
    Trinchieri, G. (1989) Biology of natural killer cells. Adv Immunol 47, 187–376.PubMedCrossRefGoogle Scholar
  126. 126.
    Bellone, G., Aste-Amezaga, M., Trinchieri, G., and Rodeck, U. (1995) Regulation of NK cell functions by TGF-beta 1. J Immunol 155, 1066–73.PubMedGoogle Scholar
  127. 127.
    Rook, A., Kehrl, J., Wakefield, L., Roberts, A., Sporn, M., Burlington, D., Lane, H., and Fauci, A. (1986) Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol 136, 3916–20.PubMedGoogle Scholar
  128. 128.
    Castriconi, R., Cantoni, C., Della Chiesa, M., Vitale, M., Marcenaro, E., Conte, R., Biassoni, R., Bottino, C., Moretta, L., and Moretta, A. (2003) Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A 100, 4120–5.PubMedCrossRefGoogle Scholar
  129. 129.
    Meadows, S., Eriksson, M., Barber, A., and Sentman, C. (2006) Human NK cell IFN-gamma production is regulated by endogenous TGF-beta. Int Immunopharmacol 6, 1020–8.PubMedCrossRefGoogle Scholar
  130. 130.
    Yu, J., Wei, M., Becknell, B., Trotta, R., Liu, S., Boyd, Z., Jaung, M., Blaser, B., Sun, J., Benson, D. J., Mao, H., Yokohama, A., Bhatt, D., Shen, L., Davuluri, R., Weinstein, M., Marcucci, G., and Caligiuri, M. (2006) Pro- and antiinflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity 24, 575–90.PubMedCrossRefGoogle Scholar
  131. 131.
    Laouar, Y., Sutterwala, F., Gorelik, L., and Flavell, R. (2005) Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. Nat Immunol 6, 600–7.PubMedCrossRefGoogle Scholar
  132. 132.
    Borkowski, T., Letterio, J., Farr, A., and Udey, M. (1996) A role for endogenous transforming growth factor beta 1 in Langerhans cell biology: the skin of transforming growth factor beta 1 null mice is devoid of epidermal Langerhans cells. J Exp Med 184, 2417–22.PubMedCrossRefGoogle Scholar
  133. 133.
    Geissmann, F., Prost, C., Monnet, J., Dy, M., Brousse, N., and Hermine, O. (1998) Transforming growth factor beta1, in the presence of granulocyte/macrophage colony-stimulating factor and interleukin 4, induces differentiation of human peripheral blood monocytes into dendritic Langerhans cells. J Exp Med 187, 961–6.PubMedCrossRefGoogle Scholar
  134. 134.
    Strobl, H., Riedl, E., Scheinecker, C., Bello-Fernandez, C., Pickl, W., Rappersberger, K., Majdic, O., and Knapp, W. (1996) TGF-beta 1 promotes in vitro development of dendritic cells from CD34+ hemopoietic progenitors. J Immunol 157, 1499–507.PubMedGoogle Scholar
  135. 135.
    Heinz, L., Platzer, B., Reisner, P., Jorgl, A., Taschner, S., Gobel, F., and Strobl, H. (2006) Differential involvement of PU.1 and Id2 downstream of TGF-beta1 during Langerhans-cell commitment. Blood 107, 1445–53.PubMedCrossRefGoogle Scholar
  136. 136.
    Faunce, D., Terajewicz, A., and Stein-Streilein, J. (2004) Cutting edge: in vitro-generated tolerogenic APC induce CD8+ T regulatory cells that can suppress ongoing experimental autoimmune encephalomyelitis. J Immunol 172, 1991–5.PubMedGoogle Scholar
  137. 137.
    Gruschwitz, M., and Hornstein, O. (1992) Expression of transforming growth factor type beta on human epidermal dendritic cells. J Invest Dermatol 99, 114–6.PubMedCrossRefGoogle Scholar
  138. 138.
    Zhang, X., Huang, H., Yuan, J., Sun, D., Hou, W., Gordon, J., and Xiang, J. (2005) CD4-8- dendritic cells prime CD4+ T regulatory 1 cells to suppress antitumor immunity. J Immunol 175, 2931–7.PubMedGoogle Scholar
  139. 139.
    Roncarolo, M., Levings, M., and Traversari, C. (2001) Differentiation of T regulatory cells by immature dendritic cells. J Exp Med 193, F5–9.PubMedCrossRefGoogle Scholar
  140. 140.
    Coombes, J. and Powrie, F. (2008) Dendritic cells in intestinal immune regulation. Nat Rev Immunol 8, 435–46.PubMedCrossRefGoogle Scholar
  141. 141.
    Coombes, J., Siddiqui, K., Arancibia-Carcamo, C., Hall, J., Sun, C., Belkaid, Y., and Powrie, F. (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 204, 1757–64.PubMedCrossRefGoogle Scholar
  142. 142.
    Pham, C. (2006) Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol 6, 541–50.PubMedCrossRefGoogle Scholar
  143. 143.
    Brandes, M., Mai, U., Ohura, K., and Wahl, S. (1991) Type I transforming growth factor-beta receptors on neutrophils mediate chemotaxis to transforming growth factor-beta. J Immunol 147, 1600–6.PubMedGoogle Scholar
  144. 144.
    Reibman, J., Meixler, S., Lee, T., Gold, L., Cronstein, B., Haines, K., Kolasinski, S., and Weissmann, G. (1991) Transforming growth factor beta 1, a potent chemoattractant for human neutrophils, bypasses classic signal-transduction pathways. Proc Natl Acad Sci U S A 88, 6805–9.PubMedCrossRefGoogle Scholar
  145. 145.
    Fridlender, Z., Sun, J., Kim, S., Kapoor, V., Cheng, G., Ling, L., Worthen, G., and Albelda, S. (2009) Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–94.PubMedCrossRefGoogle Scholar
  146. 146.
    Jinnin, M., Ihn, H., Asano, Y., Yamane, K., Trojanowska, M., and Tamaki, K. (2004) Tenascin-C upregulation by transforming growth factor-beta in human dermal fibroblasts involves Smad3, Sp1, and Ets1. Oncogene 23, 1656–67.PubMedCrossRefGoogle Scholar
  147. 147.
    Sugiyama, M., Ichida, T., Sato, T., Ishikawa, T., Matsuda, Y., and Asakura, H. (1998) Expression of activin A is increased in cirrhotic and fibrotic rat livers. Gastroenterology 114, 550–8.PubMedCrossRefGoogle Scholar
  148. 148.
    Wada, W., Kuwano, H., Hasegawa, Y., and Kojima, I. (2004) The dependence of transforming growth factor-beta-induced collagen production on autocrine factor activin A in hepatic stellate cells. Endocrinology 145, 2753–9.PubMedCrossRefGoogle Scholar
  149. 149.
    Evans, R. A., Tian, Y. C., Steadman, R., and Phillips, A. O. (2003) TGF-beta1-mediated fibroblast-myofibroblast terminal differentiation-the role of Smad proteins. Exp Cell Res 282, 90–100.PubMedCrossRefGoogle Scholar
  150. 150.
    Malmstrom, J., Lindberg, H., Lindberg, C., Bratt, C., Wieslander, E., Delander, E. L., Sarnstrand, B., Burns, J. S., Mose-Larsen, P., Fey, S., and Marko-Varga, G. (2004) Transforming growth factor-beta 1 specifically induce proteins involved in the myofibroblast contractile apparatus. Mol Cell Proteomics 3, 466–77.PubMedCrossRefGoogle Scholar
  151. 151.
    Zhu, Z., Homer, R. J., Wang, Z., Chen, Q., Geba, G. P., Wang, J., Zhang, Y., and Elias, J. A. (1999) Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 103, 779–88.PubMedCrossRefGoogle Scholar
  152. 152.
    Zhou, X., Trudeau, J. B., Schoonover, K. J., Lundin, J. I., Barnes, S. M., Cundall, M. J., and Wenzel, S. E. (2005) Interleukin-13 augments transforming growth factor-beta1-induced tissue inhibitor of metalloproteinase-1 expression in primary human airway fibroblasts. Am J Physiol Cell Physiol 288, C435–42.PubMedCrossRefGoogle Scholar
  153. 153.
    Chen, Q., Rabach, L., Noble, P., Zheng, T., Lee, C. G., Homer, R. J., and Elias, J. A. (2005) IL-11 receptor alpha in the pathogenesis of IL-13-induced inflammation and remodeling. J Immunol 174, 2305–13.PubMedGoogle Scholar
  154. 154.
    Batra, V., Musani, A. I., Hastie, A. T., Khurana, S., Carpenter, K. A., Zangrilli, J. G., and Peters, S. P. (2004) Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-beta1, TGF-beta2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on alpha-smooth muscle actin and collagen III synthesis by primary human lung fibroblasts. Clin Exp Allergy 34, 437–44.PubMedCrossRefGoogle Scholar
  155. 155.
    Schultz-Cherry, S. and Hinshaw, V. (1996) Influenza virus neuraminidase activates latent transforming growth factor beta. J Virol 70, 8624–9.PubMedGoogle Scholar
  156. 156.
    Tinoco, R., Alcalde, V., Yang, Y., Sauer, K., and Zuniga, E. (2009) Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. Immunity 31, 145–57.PubMedCrossRefGoogle Scholar
  157. 157.
    Sanjabi, S., Mosaheb, M., and Flavell, R. (2009) Opposing effects of TGF-beta and IL-15 cytokines control the number of short-lived effector CD8+ T cells. Immunity 31, 131–44.PubMedCrossRefGoogle Scholar
  158. 158.
    Omer, F., and Riley, E. (1998) Transforming growth factor beta production is inversely correlated with severity of murine malaria infection. J Exp Med 188, 39–48.PubMedCrossRefGoogle Scholar
  159. 159.
    Tsutsui, N. and Kamiyama, T. (1999) Transforming growth factor beta-induced failure of resistance to infection with blood-stage Plasmodium chabaudi in mice. Infect Immun 67, 2306–11.PubMedGoogle Scholar
  160. 160.
    Ocana-Morgner, C., Mota, M., and Rodriguez, A. (2003) Malaria blood stage suppression of liver stage immunity by dendritic cells. J Exp Med 197, 143–51.PubMedCrossRefGoogle Scholar
  161. 161.
    Ocana-Morgner, C., Wong, K., Lega, F., Dotor, J., Borras-Cuesta, F., and Rodriguez, A. (2007) Role of TGF-beta and PGE2 in T cell responses during Plasmodium yoelii infection. Eur J Immunol 37, 1562–74.PubMedCrossRefGoogle Scholar
  162. 162.
    Walther, M., Tongren, J., Andrews, L., Korbel, D., King, E., Fletcher, H., Andersen, R., Bejon, P., Thompson, F., Dunachie, S., Edele, F., de Souza, J., Sinden, R., Gilbert, S., Riley, E., and Hill, A. (2005) Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23, 287–96.PubMedCrossRefGoogle Scholar
  163. 163.
    Abath, F., Morais, C., Montenegro, C., Wynn, T., and Montenegro, S. (2006) Immunopathogenic mechanisms in schistosomiasis: what can be learnt from human studies? Trends Parasitol 22, 85–91.PubMedCrossRefGoogle Scholar
  164. 164.
    Dunne, D., and Pearce, E. (1999) Immunology of hepatosplenic schistosomiasis mansoni: a human perspective. Microbes Infect 1, 553–60.PubMedCrossRefGoogle Scholar
  165. 165.
    Herbert, D., Orekov, T., Perkins, C., and Finkelman, F. (2008) IL-10 and TGF-beta redundantly protect against severe liver injury and mortality during acute schistosomiasis. J Immunol 181, 7214–20.PubMedGoogle Scholar
  166. 166.
    de Jesus, A. R., Magalhaes, A., Miranda, D. G., Miranda, R. G., Araujo, M. I., de Jesus, A. A., Silva, A., Santana, L. B., Pearce, E., and Carvalho, E. M. (2004) Association of type 2 cytokines with hepatic fibrosis in human Schistosoma mansoni infection. Infect Immun 72, 3391–7.PubMedCrossRefGoogle Scholar
  167. 167.
    Pearce, E. J. and MacDonald, A. S. (2002) The immunobiology of schistosomiasis. Nat Rev Immunol 2, 499–511.PubMedCrossRefGoogle Scholar
  168. 168.
    Kulkarni, A. B. and Karlsson, S. (1997) Inflammation and TGF beta 1: lessons from the TGF beta 1 null mouse. Res Immunol 148, 453–6.PubMedCrossRefGoogle Scholar
  169. 169.
    Kuruvilla, A., Shah, R., Hochwald, G., Liggitt, H., Palladino, M., and Thorbecke, G. (1991) Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proc Natl Acad Sci U S A 88, 2918–21.PubMedCrossRefGoogle Scholar
  170. 170.
    Racke, M., Dhib-Jalbut, S., Cannella, B., Albert, P., Raine, C., and McFarlin, D. (1991) Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1. J Immunol 146, 3012–7.PubMedGoogle Scholar
  171. 171.
    Ohtsuka, K., Gray, J., Stimmler, M., Toro, B., and Horwitz, D. (1998) Decreased production of TGF-beta by lymphocytes from patients with systemic lupus erythematosus. J Immunol 160, 2539–45.PubMedGoogle Scholar
  172. 172.
    Kurasawa, K., Hirose, K., Sano, H., Endo, H., Shinkai, H., Nawata, Y., Takabayashi, K., and Iwamoto, I. (2000) Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum 43, 2455–63.PubMedCrossRefGoogle Scholar
  173. 173.
    Yang, J., Chu, Y., Yang, X., Gao, D., Zhu, L., Yang, X., Wan, L., and Li, M. (2009) Th17 and natural Treg cell population dynamics in systemic lupus erythematosus. Arthritis Rheum 60, 1472–83.PubMedCrossRefGoogle Scholar
  174. 174.
    Nadkarni, S., Mauri, C., and Ehrenstein, M. (2007) Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med 204, 33–9.PubMedCrossRefGoogle Scholar
  175. 175.
    Lawson, C., Brown, A., Bejarano, V., Douglas, S., Burgoyne, C., Greenstein, A., Boylston, A., Emery, P., Ponchel, F., and Isaacs, J. (2006) Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood. Rheumatology (Oxford) 45, 1210–7.CrossRefGoogle Scholar
  176. 176.
    Behrens, F., Himsel, A., Rehart, S., Stanczyk, J., Beutel, B., Zimmermann, S., Koehl, U., Moller, B., Gay, S., Kaltwasser, J., Pfeilschifter, J., and Radeke, H. (2007) Imbalance in distribution of functional autologous regulatory T cells in rheumatoid arthritis. Ann Rheum Dis 66, 1151–6.PubMedCrossRefGoogle Scholar
  177. 177.
    You, S., Alyanakian, M., Segovia, B., Damotte, D., Bluestone, J., Bach, J., and Chatenoud, L. (2008) Immunoregulatory pathways controlling progression of autoimmunity in NOD mice. Ann N Y Acad Sci 1150, 300–10.PubMedCrossRefGoogle Scholar
  178. 178.
    King, C., Davies, J., Mueller, R., Lee, M., Krahl, T., Yeung, B., O’Connor, E., and Sarvetnick, N. (1998) TGF-beta1 alters APC preference, polarizing islet antigen responses toward a Th2 phenotype. Immunity 8, 601–13.PubMedCrossRefGoogle Scholar
  179. 179.
    Moritani, M., Yoshimoto, K., Wong, S., Tanaka, C., Yamaoka, T., Sano, T., Komagata, Y., Miyazaki, J., Kikutani, H., and Itakura, M. (1998) Abrogation of autoimmune diabetes in nonobese diabetic mice and protection against effector lymphocytes by transgenic paracrine TGF-beta1. J Clin Invest 102, 499–506.PubMedCrossRefGoogle Scholar
  180. 180.
    Green, E., Gorelik, L., McGregor, C., Tran, E., and Flavell, R. (2003) CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci U S A 100, 10878–83.PubMedCrossRefGoogle Scholar
  181. 181.
    Shoda, L., Young, D., Ramanujan, S., Whiting, C., Atkinson, M., Bluestone, J., Eisenbarth, G., Mathis, D., Rossini, A., Campbell, S., Kahn, R., and Kreuwel, H. (2005) A comprehensive review of interventions in the NOD mouse and implications for translation. Immunity 23, 115–26.PubMedCrossRefGoogle Scholar
  182. 182.
    Filippi, C., Estes, E., Oldham, J., and von Herrath, M. (2009) Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice. J Clin Invest 119, 1515–23.PubMedGoogle Scholar
  183. 183.
    Mirshafiey, A., and Mohsenzadegan, M. (2009) TGF-beta as a promising option in the treatment of multiple sclerosis. Neurophar macology 56, 929-36.PubMedCrossRefGoogle Scholar
  184. 184.
    Johns, L., Flanders, K., Ranges, G., and Sriram, S. (1991) Successful treatment of experimental allergic encephalomyelitis with transforming growth factor-beta 1. J Immunol 147, 1792–6.PubMedGoogle Scholar
  185. 185.
    Johns, L. and Sriram, S. (1993) Experimental allergic encephalomyelitis: neutralizing antibody to TGF beta 1 enhances the clinical severity of the disease. J Neuroimmunol 47, 1–7.PubMedCrossRefGoogle Scholar
  186. 186.
    Morimoto, C. and Schlossman, S. (1998) The structure and function of CD26 in the T-cell immune response. Immunol Rev 161, 55–70.PubMedCrossRefGoogle Scholar
  187. 187.
    Preller, V., Gerber, A., Wrenger, S., Togni, M., Marguet, D., Tadje, J., Lendeckel, U., Rocken, C., Faust, J., Neubert, K., Schraven, B., Martin, R., Ansorge, S., Brocke, S., and Reinhold, D. (2007) TGF-beta1-mediated control of central nervous system inflammation and autoimmunity through the inhibitory receptor CD26. J Immunol 178, 4632–40.PubMedGoogle Scholar
  188. 188.
    Steinbrecher, A., Reinhold, D., Quigley, L., Gado, A., Tresser, N., Izikson, L., Born, I., Faust, J., Neubert, K., Martin, R., Ansorge, S., and Brocke, S. (2001) Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and up-regulates TGF-beta 1 secretion in vivo. J Immunol 166, 2041–8.PubMedGoogle Scholar
  189. 189.
    Wyss-Coray, T., Borrow, P., Brooker, M., and Mucke, L. (1997) Astroglial overproduction of TGF-beta 1 enhances inflammatory central nervous system disease in transgenic mice. J Neuroimmunol 77, 45–50.PubMedCrossRefGoogle Scholar
  190. 190.
    Luo, J., Ho, P., Buckwalter, M., Hsu, T., Lee, L., Zhang, H., Kim, D., Kim, S., Gambhir, S., Steinman, L., and Wyss-Coray, T. (2007) Glia-dependent TGF-beta signaling, acting independently of the TH17 pathway, is critical for initiation of murine autoimmune encephalomyelitis. J Clin Invest 117, 3306–15.PubMedCrossRefGoogle Scholar
  191. 191.
    Korn, T., Reddy, J., Gao, W., Bettelli, E., Awasthi, A., Petersen, T., Backstrom, B., Sobel, R., Wucherpfennig, K., Strom, T., Oukka, M., and Kuchroo, V. (2007) Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med 13, 423–31.PubMedCrossRefGoogle Scholar
  192. 192.
    Komiyama, Y., Nakae, S., Matsuki, T., Nambu, A., Ishigame, H., Kakuta, S., Sudo, K., and Iwakura, Y. (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177, 566–73.PubMedGoogle Scholar
  193. 193.
    Lock, C., Hermans, G., Pedotti, R., Brendolan, A., Schadt, E., Garren, H., Langer-Gould, A., Strober, S., Cannella, B., Allard, J., Klonowski, P., Austin, A., Lad, N., Kaminski, N., Galli, S., Oksenberg, J., Raine, C., Heller, R., and Steinman, L. (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8, 500–8.PubMedCrossRefGoogle Scholar
  194. 194.
    Tzartos, J., Friese, M., Craner, M., Palace, J., Newcombe, J., Esiri, M., and Fugger, L. (2008) Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172, 146–55.PubMedCrossRefGoogle Scholar
  195. 195.
    Prud’homme, G. and Piccirillo, C. (2000) The inhibitory effects of transforming growth factor-beta-1 (TGF-beta1) in autoimmune diseases. J Autoimmun 14, 23–42.PubMedCrossRefGoogle Scholar
  196. 196.
    Jones, P. and Baylin, S. (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3, 415–28.PubMedCrossRefGoogle Scholar
  197. 197.
    Russell, J. and Ley, T. (2002) Lymphocyte-mediated cytotoxicity. Annu Rev Immunol 20, 323–70.PubMedCrossRefGoogle Scholar
  198. 198.
    Shah, A., Tabayoyong, W., Kimm, S., Kim, S., Van Parijs, L., and Lee, C. (2002) Reconstitution of lethally irradiated adult mice with dominant negative TGF-beta type II receptor-transduced bone marrow leads to myeloid expansion and inflammatory disease. J Immunol 169, 3485–91.PubMedGoogle Scholar
  199. 199.
    Shah, A., Tabayoyong, W., Kundu, S., Kim, S., Van Parijs, L., Liu, V., Kwon, E., Greenberg, N., and Lee, C. (2002) Suppression of tumor metastasis by blockade of transforming growth factor beta signaling in bone marrow cells through a retroviral-mediated gene therapy in mice. Cancer Res 62, 7135–8.PubMedGoogle Scholar
  200. 200.
    Torre-Amione, G., Beauchamp, R., Koeppen, H., Park, B., Schreiber, H., Moses, H., and Rowley, D. (1990) A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. Proc Natl Acad Sci U S A 87, 1486–90.PubMedCrossRefGoogle Scholar
  201. 201.
    Thomas, D., and Massague, J. (2005) TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8, 369–80.PubMedCrossRefGoogle Scholar
  202. 202.
    di Bari, M., Lutsiak, M., Takai, S., Mostbock, S., Farsaci, B., Semnani, R., Wakefield, L., Schlom, J., and Sabzevari, H. (2009) TGF-beta modulates the functionality of tumor-infiltrating CD8+ T cells through effects on TCR signaling and Spred1 expression. Cancer Immunol Immunother 58, 1811–20.Google Scholar
  203. 203.
    Nam, J., Terabe, M., Mamura, M., Kang, M., Chae, H., Stuelten, C., Kohn, E., Tang, B., Sabzevari, H., Anver, M., Lawrence, S., Danielpour, D., Lonning, S., Berzofsky, J., and Wakefield, L. (2008) An anti-transforming growth factor beta antibody suppresses metastasis via cooperative effects on mul tiple cell compartments. Cancer Res 68, 3835–43.PubMedCrossRefGoogle Scholar
  204. 204.
    Vivier, E., Tomasello, E., Baratin, M., Walzer, T., and Ugolini, S. (2008) Functions of natural killer cells. Nat Immunol 9, 503–10.PubMedCrossRefGoogle Scholar
  205. 205.
    Horng, T., Bezbradica, J., and Medzhitov, R. (2007) NKG2D signaling is coupled to the interleukin 15 receptor signaling pathway. Nat Immunol 8, 1345–52.PubMedCrossRefGoogle Scholar
  206. 206.
    Ghiringhelli, F., Menard, C., Terme, M., Flament, C., Taieb, J., Chaput, N., Puig, P., Novault, S., Escudier, B., Vivier, E., Lecesne, A., Robert, C., Blay, J., Bernard, J., Caillat-Zucman, S., Freitas, A., Tursz, T., Wagner-Ballon, O., Capron, C., Vainchencker, W., Martin, F., and Zitvogel, L. (2005) CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 202, 1075–85.PubMedCrossRefGoogle Scholar
  207. 207.
    Friese, M., Wischhusen, J., Wick, W., Weiler, M., Eisele, G., Steinle, A., and Weller, M. (2004) RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res 64, 7596–603.PubMedCrossRefGoogle Scholar
  208. 208.
    Levy, L., and Hill, C. (2006) Alterations in components of the TGF-beta superfamily signaling pathways in human cancer. Cytokine Growth Factor Rev 17, 41–58.PubMedCrossRefGoogle Scholar
  209. 209.
    Ruiz-Ortega, M., Rodriguez-Vita, J., Sanchez-Lopez, E., Carvajal, G., and Egido, J. (2007) TGF-beta signaling in vascular fibrosis. Cardiovasc Res 74, 196–206.PubMedCrossRefGoogle Scholar
  210. 210.
    Friess, H. and Buchler, M. (1993) Growth factors in pancreatic cancer: the key to new therapy concepts for the future? Z Gastroenterol 31, 629–30.PubMedGoogle Scholar
  211. 211.
    Gorsch, S., Memoli, V., Stukel, T., Gold, L., and Arrick, B. (1992) Immunohistochemical staining for transforming growth factor beta 1 associates with disease progression in human breast cancer. Cancer Res 52, 6949–52.PubMedGoogle Scholar
  212. 212.
    Teicher, B. (2007) Transforming growth factor-beta and the immune response to malignant disease. Clin Cancer Res 13, 6247–51.PubMedCrossRefGoogle Scholar
  213. 213.
    Pollard, J. (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4, 71–8.PubMedCrossRefGoogle Scholar
  214. 214.
    Ivanovic, V., Demajo, M., Krtolica, K., Krajnovic, M., Konstantinovic, M., Baltic, V., Prtenjak, G., Stojiljkovic, B., Breberina, M., Neskovic-Konstantinovic, Z., Nikolic-Vukosavljevic, D., and Dimitrijevic, B. (2006) Elevated plasma TGF-beta1 levels correlate with decreased survival of metastatic breast cancer patients. Clin Chim Acta 371, 191–3.PubMedCrossRefGoogle Scholar
  215. 215.
    Larmonier, N., Marron, M., Zeng, Y., Cantrell, J., Romanoski, A., Sepassi, M., Thompson, S., Chen, X., Andreansky, S., and Katsanis, E. (2007) Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. Cancer Immunol Immunother 56, 48–59.PubMedCrossRefGoogle Scholar
  216. 216.
    Mao, C., Wang, S., Jiang, Q., Tong, J., Ma, J., Yang, M., Xu, X., Qiu, G., Shao, Q., Li, L., and Xu, H. (2008) Increased CD4CD25+FOXP3+ regulatory T Cells in cancer patients from conversion of CD4+CD25- T cells through tumor-derived factors. Onkologie 31, 243–8.PubMedCrossRefGoogle Scholar
  217. 217.
    Zhao, X., Ye, F., Chen, L., Lu, W., and Xie, X. (2009) Human epithelial ovarian carcinoma cell-derived cytokines cooperatively induce activated CD4(+)CD25(−)CD45RA(+) naive T cells to express forkhead box protein 3 and exhibit suppressive ability in vitro. Cancer Sci 100, 2143–51.PubMedCrossRefGoogle Scholar
  218. 218.
    Clark, R., Huang, S., Murphy, G., Mollet, I., Hijnen, D., Muthukuru, M., Schanbacher, C., Edwards, V., Miller, D., Kim, J., Lambert, J., and Kupper, T. (2008) Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells. J Exp Med 205, 2221–34.PubMedCrossRefGoogle Scholar
  219. 219.
    Curiel, T., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J., Zhang, L., Burow, M., Zhu, Y., Wei, S., Kryczek, I., Daniel, B., Gordon, A., Myers, L., Lackner, A., Disis, M., Knutson, K., Chen, L., and Zou, W. (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10, 942–9.PubMedCrossRefGoogle Scholar
  220. 220.
    Zhang, Q., Yang, X., Pins, M., Javonovic, B., Kuzel, T., Kim, S., Parijs, L., Greenberg, N., Liu, V., Guo, Y., and Lee, C. (2005) Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer. Cancer Res 65, 1761–9.PubMedCrossRefGoogle Scholar
  221. 221.
    Poutahidis, T., Haigis, K., Rao, V., Nambiar, P., Taylor, C., Ge, Z., Watanabe, K., Davidson, A., Horwitz, B., Fox, J., and Erdman, S. (2007) Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma. Carcinogenesis 28, 2614–23.PubMedCrossRefGoogle Scholar
  222. 222.
    Garrett, W., Punit, S., Gallini, C., Michaud, M., Zhang, D., Sigrist, K., Lord, G., Glickman, J., and Glimcher, L. (2009) Colitis-associated colorectal cancer driven by T-bet deficiency in dendritic cells. Cancer Cell 16, 208–19.PubMedCrossRefGoogle Scholar
  223. 223.
    Coussens, L. and Werb, Z. (2002) Infla mmation and cancer. Nature 420, 860–7.PubMedCrossRefGoogle Scholar
  224. 224.
    Lin, W. and Karin, M. (2007) A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 117, 1175–83.PubMedCrossRefGoogle Scholar
  225. 225.
    Monteleone, G., Mann, J., Monteleone, I., Vavassori, P., Bremner, R., Fantini, M., Del Vecchio Blanco, G., Tersigni, R., Alessandroni, L., Mann, D., Pallone, F., and MacDonald, T. (2004) A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gut inflammation. J Biol Chem 279, 3925–32.PubMedCrossRefGoogle Scholar
  226. 226.
    Kopp, H., Placke, T., and Salih, H. (2009) Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Cancer Res 69, 7775–83.PubMedCrossRefGoogle Scholar
  227. 227.
    Liu, S., Tsai, J., Shen, C., Sher, Y., Hsieh, C., Yeh, Y., Chou, A., Chang, S., Hsiao, K., Yu, F., and Chen, H. (2007) Induction of a distinct CD8 Tnc17 subset by transforming growth factor-beta and interleukin-6. J Leukoc Biol 82, 354–60.PubMedCrossRefGoogle Scholar
  228. 228.
    Nam, J., Terabe, M., Kang, M., Chae, H., Voong, N., Yang, Y., Laurence, A., Michalowska, A., Mamura, M., Lonning, S., Berzofsky, J., and Wakefield, L. (2008) Transforming growth factor beta subverts the immune system into directly promoting tumor growth through interleukin-17. Cancer Res 68, 3915–23.PubMedCrossRefGoogle Scholar
  229. 229.
    Numasaki, M., Lotze, M., and Sasaki, H. (2004) Interleukin-17 augments tumor necrosis factor-alpha-induced elaboration of proangiogenic factors from fibroblasts. Immunol Lett 93, 39–43.PubMedCrossRefGoogle Scholar
  230. 230.
    Takahashi, H., Numasaki, M., Lotze, M., and Sasaki, H. (2005) Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells. Immunol Lett 98, 189–93.PubMedCrossRefGoogle Scholar
  231. 231.
    Kryczek, I., Wei, S., Zou, L., Altuwaijri, S., Szeliga, W., Kolls, J., Chang, A., and Zou, W. (2007) Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol 178, 6730–3.PubMedGoogle Scholar
  232. 232.
    Sfanos, K., Bruno, T., Maris, C., Xu, L., Thoburn, C., DeMarzo, A., Meeker, A., Isaacs, W., and Drake, C. (2008) Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res 14, 3254–61.PubMedCrossRefGoogle Scholar
  233. 233.
    Zhu, X., Mulcahy, L., Mohammed, R., Lee, A., Franks, H., Kilpatrick, L., Yilmazer, A., Paish, E., Ellis, I., Patel, P., and Jackson, A. (2008) IL-17 expression by breast-cancer-associated macrophages: IL-17 promotes invasiveness of breast cancer cell lines. Breast Cancer Res 10, R95.PubMedCrossRefGoogle Scholar
  234. 234.
    Kryczek, I., Banerjee, M., Cheng, P., Vatan, L., Szeliga, W., Wei, S., Huang, E., Finlayson, E., Simeone, D., Welling, T., Chang, A., Coukos, G., Liu, R., and Zou, W. (2009) Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 114, 1141–9.PubMedCrossRefGoogle Scholar
  235. 235.
    Miyahara, Y., Odunsi, K., Chen, W., Peng, G., Matsuzaki, J., and Wang, R. (2008) Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Natl Acad Sci U S A 105, 15505–10.PubMedCrossRefGoogle Scholar
  236. 236.
    Murugaiyan, G. and Saha, B. (2009) Protumor vs antitumor functions of IL-17. J Immunol 183, 4169–75.PubMedCrossRefGoogle Scholar
  237. 237.
    Wu, S., Rhee, K., Albesiano, E., Rabizadeh, S., Wu, X., Yen, H., Huso, D., Brancati, F., Wick, E., McAllister, F., Housseau, F., Pardoll, D., and Sears, C. (2009) A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15, 1016–22.PubMedCrossRefGoogle Scholar
  238. 238.
    Martin-Orozco, N., Muranski, P., Chung, Y., Yang, X., Yamazaki, T., Lu, S., Hwu, P., Restifo, N., Overwijk, W., and Dong, C. (2009) T helper 17 cells promote cytotoxic T cell activation in tumor immunity. Immu nity 31, 787–98.PubMedCrossRefGoogle Scholar
  239. 239.
    Yang, L. and Moses, H. (2008) Transforming growth factor beta: tumor suppressor or promoter? Are host immune cells the answer? Cancer Res 68, 9107–11.PubMedCrossRefGoogle Scholar
  240. 240.
    Mayor, C., Brudno, M., Schwartz, J. R., Poliakov, A., Rubin, E. M., Frazer, K. A., Pachter, L. S., and Dubchak, I. (2000) VISTA : visualizing global DNA sequence alignments of arbitrary length. Bioinformatics 16, 1046–7.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press 2010

Authors and Affiliations

  1. 1.Department of Immunology and Infectious Diseases, Harvard School of Public HealthHarvard UniversityBostonUSA
  2. 2.Allergy and Clinical ImmunologyNational Heart and Lung Institute, Imperial CollegeLondonUK

Personalised recommendations