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Regulatory T Cells and Clinical Application pp 111–134Cite as

TGF-β Regulates Reciprocal Differentiation of CD4+CD25+Foxp3+ Regulatory T Cells and IL-17-Producing Th17 Cells from Naïve CD4+CD25– T Cells

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Abstract

CD4+CD25+ T cells expressing forkhead transcription factor Foxp3 are recognized as professional regulatory T cells (Tregs) and are instrumental in the induction and maintenance of immune tolerance. In addition to their development intrathymically, CD4+ CD25+Foxp3+ Tregs may also be converted extrathymically from CD4+CD25– naïve T cells through induction of Foxp3 by transforming growth factor–beta (TGF-β). Most recently, an interleukin-17 (IL-17)-producing pro-inflammatory T helper (Th) subset, designated Th17, has been identified. Unexpectedly, the differentiation of Th17 cells from CD4+CD25– naïve T cells also requires TGF-β, but in the presence of the proinflammatory cytokine interleukin-6 (IL-6). The transcription factor that programs and directs Th17 cell differentiation includes retinoic-acid-related orphan receptor-γt (RORrt), which is induced by the combined signals from both IL-6 and TGF-β engagement. This chapter attempts to highlight the discovery and development of the TGF-β reciprocal regulation of Tregs and Th17 cells.

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References

  1. Mosmann, T. R., H. Cherwinski, M. W. Bond, M. A. Giedin, and R. L. Coffman. 1986. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348.

    PubMed  CAS  Google Scholar 

  2. Seder, R. A., and W. E. Paul. 1994. Acuisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol 12:635.

    Article  PubMed  CAS  Google Scholar 

  3. Sakaguchi, S., N. Sakaguchi, M. Asano, M. Itoh, and M. Toda. 1995. 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 155:1151.

    PubMed  CAS  Google Scholar 

  4. Shevach, E. M. 2001. Certified professionals: CD4(+)CD25(+) suppressor T cells. J Exp Med 193:F41.

    Article  PubMed  CAS  Google Scholar 

  5. Chen, W., W. Jin, N. Hardegen, K. J. Lei, L. Li, N. Marinos, G. McGrady, and S. M. Wahl. 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.

    Article  PubMed  CAS  Google Scholar 

  6. Fantini, M. C., C. Becker, G. Monteleone, F. Pallone, P. R. Galle, and M. F. Neurath. 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.

    PubMed  CAS  Google Scholar 

  7. Wan, Y. Y., and R. A. Flavell. 2005. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci USA 102:5126.

    Article  PubMed  CAS  Google Scholar 

  8. Bettelli, E., Y. Carrier, W. Gao, T. Korn, T. B. Strom, M. Oukka, H. L. Weiner, and V. K. Kuchroo. 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235.

    Article  PubMed  CAS  Google Scholar 

  9. Dong, C. 2006. Diversification of T-helper-cell lineages: Finding the family root of IL-17-producing cells. Nat Rev Immunol 6:329.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. Murphy, C. A., C. L. Langrish, Y. Chen, W. Blumenschein, T. McClanahan, R. A. Kastelein, J. D. Sedgwick, and D. J. Cua. 2003. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198:1951.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  13. Murphy, K., A. Heimberger, and D. Loh. 1990. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science 250:1720.

    Article  PubMed  CAS  Google Scholar 

  14. Murphy, K. M., and S. L. Reiner. 2002. The lineage decisions of helper T cells. Nat Rev Immunol 2:933.

    Article  PubMed  CAS  Google Scholar 

  15. Szabo, S. J., S. T. Kim, G. L. Costa, X. Zhang, C. G. Fathman, and L. H. Glimcher. 2000. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655.

    Article  PubMed  CAS  Google Scholar 

  16. Ouyang, W., S. H. Ranganath, K. Weindel, D. Bhattacharya, T. L. Murphy, W. C. Sha, and K. M. Murphy. 1998. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity 9:745.

    Article  PubMed  CAS  Google Scholar 

  17. Zheng, W., and R. A. Flavell. 1997. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89:587.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. Fontenot, J. D., M. A. Gavin, and A. Y. Rudensky. 2003. Foxp3 programs the development and function of CD4(+)CD25(+) regulatory T cells. Nat Immunol 4:330.

    Article  PubMed  CAS  Google Scholar 

  20. Hori, S., T. Takahashi, and S. Sakaguchi. 2003. Control of autoimmunity by naturally arising regulatory CD4+ T cells. Adv Immunol 81:331.

    Article  PubMed  CAS  Google Scholar 

  21. Khattri, R., T. Cox, S. A. Yasayko, and F. Ramsdell. 2003. An essential role for Scurfin in CD4(+)CD25(+) T regulatory cells. Nat Immunol 4:337.

    Article  PubMed  CAS  Google Scholar 

  22. Thornton, A. M., and E. M. Shevach. 1998. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188:287.

    Article  PubMed  CAS  Google Scholar 

  23. Bluestone, J. A., and A. K. Abbas. 2003. Natural versus adaptive regulatory T cells. Nat Rev Immunol 3:253.

    Article  PubMed  CAS  Google Scholar 

  24. Chen, W., and S. M. Wahl. 2003. TGF-beta: The missing link in CD4(+)CD25(+) regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev 14:85.

    Article  PubMed  CAS  Google Scholar 

  25. Fontenot, J. D., J. P. Rasmussen, L. M. Williams, J. L. Dooley, A. G. Farr, and A. Y. Rudensky. 2005. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329.

    Article  PubMed  CAS  Google Scholar 

  26. Sakaguchi, S. 2000. Regulatory T cells: Key controllers of immunologic self-tolerance. Cell 101:455.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  28. von Boehmer, H. 2005. Mechanisms of suppression by suppressor T cells. Nat Immunol 6:338.

    Article  CAS  Google Scholar 

  29. Baecher-Allan, C., J. A. Brown, G. J. Freeman, and D. A. Hafler. 2001. CD4+CD25 high regulatory cells in human peripheral blood. J Immunol 167:1245.

    PubMed  CAS  Google Scholar 

  30. Sakaguchi, S. 2002. Immunologic tolerance maintained by regulatory T cells: Implications for autoimmunity, tumor immunity and transplantation tolerance. Vox Sang 1(Suppl 83):151.

    Article  Google Scholar 

  31. Klein, L., K. Khazaie, and H. Von Boehmer. 2003. In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc Natl Acad Sci USA 100:8886.

    Article  PubMed  CAS  Google Scholar 

  32. Roncarolo, M. G., R. Bacchetta, C. Bordignon, S. Narula, and M. K. Levings. 2001. Type 1 T regulatory cells. Immunol Rev 182:68.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  34. Cua, D. J., and R. A. Kastelein. 2006. TGF-beta, a 'double agent' in the immune pathology war. Nat Immunol 7:557.

    Article  PubMed  CAS  Google Scholar 

  35. Aggarwal, S., N. Ghilardi, M. H. Xie, F. J. de Sauvage, and A. L. Gurney. 2003. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278:1910.

    Article  PubMed  CAS  Google Scholar 

  36. Shi, Y., and J. Massague. 2003. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685.

    Article  PubMed  CAS  Google Scholar 

  37. Chen, W., and S. M. Wahl. 2002. TGF-beta: Receptors, signaling pathways and autoimmunity. Curr Dir Autoimmun 5:62.

    Article  PubMed  CAS  Google Scholar 

  38. Strober, W., B. Kesall, I. Fuss, T. Marth, B. Ludviksson, R. Ehrhardt, and M. Neurath. 1997. Reciprocal IFN-γ and TGF-β response regulate the occurrence of mucosal inflammation. Immunol Today 18:61.

    Article  PubMed  CAS  Google Scholar 

  39. Wahl, S. M. 1994. Transforming growth factor: The good, the bad, and the ugly. J Exp Med 180:1587.

    Article  PubMed  CAS  Google Scholar 

  40. Weiner, H. L. 1997. Oral tolerance: Immune mechanisms and treatment of autoimmune diseases. Immunol Today 18:335.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  42. Kulkarni, A. B., C.-H. Huh, D. Becker, A. Gerser, M. Lyght, K. C. Flanders, A. B. Roberts, M. B. Sporn, J. M. Ward, and S. Karlsson. 1993. Transforming growth factor-β null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 90:770.

    Article  PubMed  CAS  Google Scholar 

  43. Shull, M. M., I. Ormsby, A. B. Kier, S. Pawlowski, R. J. Diebold, M.Yin, R.Allen, C. Sidman, B. Proetzel, D. calvin, N. Annuniziata, and T. Doeschman. 1992. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359:693.

    Article  PubMed  CAS  Google Scholar 

  44. Massague, J. 1998. TGF-β signal transduction. Annu Rev Biochem 67:753.

    Article  PubMed  CAS  Google Scholar 

  45. Cerwenka, A., D. Bevec, O. Majdic, W. Knapp, and W. Holter. 1994. TGF-β1 is a potent inducer of human effector T cells. J Immunol 153:4367.

    PubMed  CAS  Google Scholar 

  46. Chen, W., W. Jin, H. Tian, P. Sicurello, M. Frank, J. M. Orenstein, and S. M. Wahl. 2001. Requirement for Transforming Growth Factor beta1 in Controlling T Cell Apoptosis. J Exp Med 194:439.

    Article  PubMed  CAS  Google Scholar 

  47. Kehrl, J. H., L. M. Wakefield, A. B. Roberts, S. Jakowelw, M. Alvarez-Mon, R. Derynck, M. B. Sporn, and A. S. Fauci. 1986. Production of transforming growth factor β by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med 163:1037.

    Article  PubMed  CAS  Google Scholar 

  48. Fontenot, J. D., J. L. Dooley, A. G. Farr, and A. Y. Rudensky. 2005. Developmental regulation of Foxp3 expression during ontogeny. J Exp Med 202:901.

    Article  PubMed  CAS  Google Scholar 

  49. Tai, X., M. Cowan, L. Feigenbaum, and A. Singer. 2005. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol 6:152.

    Article  PubMed  CAS  Google Scholar 

  50. Liu, Y., S. Amarnath, and W. Chen. 2006. Requirement of CD28 signaling in homeostasis/survival of TGF-beta converted CD4+CD25+ Tregs from thymic CD4+CD25– single positive t cells. Transplantation 82:953.

    Article  PubMed  Google Scholar 

  51. Watanabe, N., Y. H. Wang, H. K. Lee, T. Ito, Y. H. Wang, W. Cao, and Y. J. Liu. 2005. Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436:1181.

    Article  PubMed  CAS  Google Scholar 

  52. Schwartz, R. H. 1996. Models of T cell anergy is there a common molecular mechanism. J Exp Med 184:1.

    Article  PubMed  CAS  Google Scholar 

  53. Schwartz, R. H. 2002. T Cell Anergy. Annu Rev Immunol 21:305.

    Google Scholar 

  54. Thompson, C. B., and J. P. Allison. 1997. The emerging role of CTLA-4 as an immune attenuator. Immunity 7:445.

    Article  PubMed  CAS  Google Scholar 

  55. Salomon, B., D. J. Lenschow, L. Rhee, N. Ashourian, B. Singh, A. Sharpe, and J. A. Bluestone. 2000. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431.

    Article  PubMed  CAS  Google Scholar 

  56. Malek, T. R., and A. L. Bayer. 2004. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 4:665.

    Article  PubMed  CAS  Google Scholar 

  57. Fontenot, J. D., J. P. Rasmussen, M. A. Gavin, and A. Y. Rudensky. 2005. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6:1142.

    Article  PubMed  CAS  Google Scholar 

  58. Antov, A., L. Yang, M. Vig, D. Baltimore, and L. Van Parijs. 2003. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. J Immunol 171:3435.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  60. Fu, S., N. Zhang, A. C. Yopp, D. Chen, M. Mao, D. Chen, H. Zhang, Y. Ding, and J. S. Bromberg. 2004. TGF-beta induces Foxp3 + T-regulatory cells from CD4 + CD25 – precursors. Am J Transplant 4:1614.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  62. Marie, J. C., D. Liggitt, and A. Y. Rudensky. 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.

    Article  PubMed  CAS  Google Scholar 

  63. Kretschmer, K., I. Apostolou, D. Hawiger, K. Khazaie, M. C. Nussenzweig, and H. von Boehmer. 2005. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6:1219.

    Article  PubMed  CAS  Google Scholar 

  64. Sakaguchi, S. 2003. Control of immune responses by naturally arising CD4+ regulatory T cells that express toll-like receptors. J Exp Med 197:397.

    Article  PubMed  CAS  Google Scholar 

  65. Schwartz, R. H. 2005. Natural regulatory T cells and self-tolerance. Nat Immunol 6:327.

    Article  PubMed  CAS  Google Scholar 

  66. Sakaguchi, S. 2003. The origin of FOXP3-expressing CD4+ regulatory T cells: Thymus or periphery. J Clin Invest 112:1310.

    PubMed  CAS  Google Scholar 

  67. Horwitz, D. A., S. G. Zheng, J. D. Gray, J. H. Wang, K. Ohtsuka, and S. Yamagiwa. 2004. Regulatory T cells generated ex vivo as an approach for the therapy of autoimmune disease. Semin Immunol 16:135.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  69. Zheng, S. G., J. H. Wang, J. D. Gray, H. Soucier, and D. A. Horwitz. 2004. Natural and induced CD4+CD25+ cells educate CD4+CD25– cells to develop suppressive activity: The role of IL-2, TGF-beta, and IL-10. J Immunol 172:5213.

    PubMed  CAS  Google Scholar 

  70. Chen, W., and S. M. Wahl. 1999. Manipulation of TGF-beta to control autoimmune and chronic inflammatory diseases. Microbes Infect 1:1367.

    Article  PubMed  CAS  Google Scholar 

  71. Swain, S. L. 1994. Generation and in vivo persistence of polarized Th1 and Th2 memory cells. Immunity 1:543.

    Article  PubMed  CAS  Google Scholar 

  72. Oida, T., L. Xu, H. L. Weiner, A. Kitani, and W. Strober. 2006. TGF-beta-mediated suppression by CD4+CD25+ T cells is facilitated by CTLA-4 signaling. J Immunol 177:2331.

    PubMed  CAS  Google Scholar 

  73. Nakamura, K., A. Kitani, I. Fuss, A. Pedersen, N. Harada, H. Nawata, and W. Strober. 2004. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol 172:834.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  75. Oida, T., X. Zhang, M. Goto, S. Hachimura, M. Totsuka, S. Kaminogawa, and H. L. Weiner. 2003. CD4+CD25– T cells that express latency-associated peptide on the surface suppress CD4+CD45RBhigh-induced colitis by a TGF-beta-dependent mechanism. J Immunol 170:2516.

    PubMed  CAS  Google Scholar 

  76. Oldenhove, G., M. de Heusch, G. Urbain-Vansanten, J. Urbain, C. Maliszewski, O. Leo, and M. Moser. 2003. CD4+ CD25+ regulatory T cells control T helper cell type 1 responses to foreign antigens induced by mature dendritic cells in vivo. J Exp Med 198:259.

    Article  PubMed  CAS  Google Scholar 

  77. Liu, Y., I. Teige, B. Birnir, and S. Issazadeh-Navikas. 2006. Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat Med 12:518.

    Article  PubMed  CAS  Google Scholar 

  78. Chen, W. 2006. Dendritic cells and (CD4+)CD25+ T regulatory cells: Crosstalk between two professionals in immunity versus tolerance. Front Biosci 11:1360.

    Article  PubMed  CAS  Google Scholar 

  79. Zhang, X., L. Izikson, L. Liu, and H. L. Weiner. 2001. Activation of CD25(+)CD4(+) regulatory T cells by oral antigen administration. J Immunol 167:4245.

    PubMed  CAS  Google Scholar 

  80. Cacoub, P., L. Musset, P. Hausfater, P. Ghillani, F. L. Fabiani, F. Charlotte, E. Angevin, P. Opolon, T. Poynard, J. C. Piette, and B. Autran. 1998. No evidence for abnormal immune activation in peripheral blood T cells in patients with hepatitis C virus (HCV) infection with or without cryoglobulinaemia. Multivirc Group. Clin Exp Immunol 113:48.

    Article  PubMed  CAS  Google Scholar 

  81. Gui, S. Y., W. Wei, H. Wang, L. Wu, W. Y. Sun, W. B. Chen, and C. Y. Wu. 2006. Effects and mechanisms of crude astragalosides fraction on liver fibrosis in rats. J Ethnopharmacol 103:154.

    Article  PubMed  Google Scholar 

  82. Walker, L. S., A. Chodos, M. Eggena, H. Dooms, and A. K. Abbas. 2003. Antigen-dependent Proliferation of CD4+ CD25+ Regulatory T Cells In Vivo. J Exp Med 198:249.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  84. von Boehmer, H., I. Aifantis, F. Gounari, O. Azogui, L. Haughn, I. Apostolou, E. Jaeckel, F. Grassi, and L. Klein. 2003. Thymic selection revisited: How essential is it? Immunol Rev 191:62.

    Article  Google Scholar 

  85. Apostolou, I., A. Sarukhan, L. Klein, and H. von Boehmer. 2002. Origin of regulatory T cells with known specificity for antigen. Nat Immunol 3:756.

    PubMed  CAS  Google Scholar 

  86. Liang, S., P. Alard, Y. Zhao, S. Parnell, S. L. Clark, and M. M. Kosiewicz. 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.

    Article  PubMed  CAS  Google Scholar 

  87. Apostolou, I., and H. von Boehmer. 2004. In vivo instruction of suppressor commitment in naive T cells. J Exp Med 199:1401.

    Article  PubMed  CAS  Google Scholar 

  88. Cobbold, S. P., R. Castejon, E. Adams, D. Zelenika, L. Graca, S. Humm, and H. Waldmann. 2004. Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 172:6003.

    PubMed  CAS  Google Scholar 

  89. Luo, X., H. Yang, I. S. Kim, F. Saint-Hilaire, D. A. Thomas, B. P. De, E. Ozkaynak, T. Muthukumar, W. W. Hancock, R. G. Crystal, and M. Suthanthiran. 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  92. Zou, W. 2006. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6:295.

    Article  PubMed  CAS  Google Scholar 

  93. Valzasina, B., S. Piconese, C. Guiducci, and M. P. Colombo. 2006. Tumor-induced expansion of regulatory T cells by conversion of CD4+CD25– lymphocytes is thymus and proliferation independent. Cancer Res 66:4488.

    Article  PubMed  CAS  Google Scholar 

  94. Fadok, V. A., D. L. Bratton, A. Konowal, P. W. Freed, J. Y. Westcott, and P. M. Henson. 1998. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101:890.

    Article  PubMed  CAS  Google Scholar 

  95. Koonpaew, S., S. Shen, L. Flowers, and W. Zhang. 2006. LAT-mediated signaling in CD4+CD25+ regulatory T cell development. J Exp Med 203:119.

    Article  PubMed  CAS  Google Scholar 

  96. Walker, M. R., D. J. Kasprowicz, V. H. Gersuk, A. Benard, M. Van Landeghen, J. H. Buckner, and S. F. Ziegler. 2003. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25– T cells. J Clin Invest 112:1437.

    PubMed  CAS  Google Scholar 

  97. Gavin, M. A., T. R. Torgerson, E. Houston, P. DeRoos, W. Y. Ho, A. Stray-Pedersen, E. L. Ocheltree, P. D. Greenberg, H. D. Ochs, and A. Y. Rudensky. 2006. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci USA 103:6659.

    Article  PubMed  CAS  Google Scholar 

  98. Schwartz, R. H. 1989. Acquisition of immunologic self-tolerance. Cell 57:1073.

    Article  PubMed  CAS  Google Scholar 

  99. Oppmann, B., R. Lesley, B. Blom, J. C. Timans, Y. Xu, B. Hunte, F. Vega, N. Yu, J. Wang, K. Singh, F. Zonin, E. Vaisberg, T. Churakova, M. Liu, D. Gorman, J. Wagner, S. Zurawski, Y. Liu, J. S. Abrams, K. W. Moore, D. Rennick, R. de Waal-Malefyt, C. Hannum, J. F. Bazan, and R. A. Kastelein. 2000. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715.

    Article  PubMed  CAS  Google Scholar 

  100. Cua, D. J., J. Sherlock, Y. Chen, C. A. Murphy, B. Joyce, B. Seymour, L. Lucian, W. To, S. Kwan, T. Churakova, S. Zurawski, M. Wiekowski, S. A. Lira, D. Gorman, R. A. Kastelein, and J. D. Sedgwick. 2003. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744.

    Article  PubMed  CAS  Google Scholar 

  101. Nakae, S., A. Nambu, K. Sudo, and Y. Iwakura. 2003. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 171:6173.

    PubMed  CAS  Google Scholar 

  102. Nakae, S., S. Saijo, R. Horai, K. Sudo, S. Mori, and Y. Iwakura. 2003. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci USA 100:5986.

    Article  PubMed  CAS  Google Scholar 

  103. Koenders, M. I., E. Lubberts, B. Oppers-Walgreen, L. van den Bersselaar, M. M. Helsen, F. E. Di Padova, A. M. Boots, H. Gram, L. A. Joosten, and W. B. van den Berg. 2005. Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1. Am J Pathol 167:141.

    Article  PubMed  CAS  Google Scholar 

  104. Pasare, C., and R. Medzhitov. 2003. Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells. Science 299:1033.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  106. Ivanov, II, B. S. McKenzie, L. Zhou, C. E. Tadokoro, A. Lepelley, J. J. Lafaille, D. J. Cua, and D. R. Littman. 2006. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121.

    Google Scholar 

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Acknowledgement

This research was supported by the Intramural Research Program of the NIH, National Institute for Dental and Craniofacial Research.

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  1. Mucosal Immunology Unit, OIIB, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA

    Wanjun Chen

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  1. Wanjun Chen
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    Chen, W. (2008). TGF-β Regulates Reciprocal Differentiation of CD4+CD25+Foxp3+ Regulatory T Cells and IL-17-Producing Th17 Cells from Naïve CD4+CD25– T Cells. In: Jiang, S. (eds) Regulatory T Cells and Clinical Application. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77909-6_7

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