Cell Biochemistry and Biophysics

, Volume 48, Issue 2–3, pp 165–175 | Cite as

Treg in type 1 diabetes

  • Todd Brusko
  • Mark AtkinsonEmail author
Original Paper


At the time of this writing, a major void exists; the lack of a method to prevent and/or reverse type 1 diabetes in humans. We believe this void to a large extent is the result of our lack in understanding the mechanisms of autoimmunity that underlie β cell destruction, a failure to understand the immunologic factors that contribute to type 1 diabetes, and the absence of immunologic tools which would allow for a better understanding of the mechanisms underlying disease development and monitoring of therapeutic interventions. Due to this, an intense degree of research interest has recently been generated to understand the mechanisms that regulate the immune response and form a state of immunological tolerance. While some progress has been made towards these goals, additional investigations are needed to address the aforementioned knowledge voids including the role for regulatory T cells (Treg), defined by their co-expression of CD4 and CD25 as well as the transcription factor FOXP3, in the pathogenesis and natural history of type 1 diabetes. We and others have recently reported findings related to the frequency and function of Treg cells in type 1 diabetes, yet the resulting literature represents a somewhat conflicting body of findings. Our studies did not support the notion that altered Treg frequencies are associated with type 1 diabetes, but rather did identify alterations in the functional (i.e., suppressive) activities of these cells in subjects with the disease. The need to bring resolution to the aforementioned published discrepancies in frequency and function of Treg in type 1 diabetes represents the impetus for this critical review. In addition, we hope to highlight the need for expanded studies that address specific knowledge gaps regarding the cellular and molecular mechanism(s) related to the frequency and function of Treg.


Autoimmunity Regulatory T cells Diabetes mellitus, Type 1 CD4+CD25+ T Cells 



Type 1 diabetes


CD4+CD25+ regulatory T cell


CD4+CD25 effector T cell


Fluorescence activated cell sorting


Magnetic-bead cell sorting


Non-obese diabetic mouse


Transforming growth factor beta


  1. 1.
    Atkinson, M. A., & Eisenbarth, G. S. (2001). Type 1 diabetes: New perspectives on disease pathogenesis and treatment. Lancet, 358, 221–229.PubMedCrossRefGoogle Scholar
  2. 2.
    Bach, J. F., & Chatenoud, L. (2001). Tolerance to islet autoantigens in type 1 diabetes. Annual Review of Immunology, 19, 131–161.PubMedCrossRefGoogle Scholar
  3. 3.
    Beard, M. E., Willis, J. A., Scott, R. S., & Nesbit, J. W. (2002). Is type 1 diabetes transmissible by bone marrow allograft? Diabetes Care, 25, 799–800.PubMedCrossRefGoogle Scholar
  4. 4.
    Serreze, D. V., & Leiter, E. H. (2003). Tracking autoimmune T cells in diabetes. Journal of Clinical Investigation, 112, 826–828.PubMedCrossRefGoogle Scholar
  5. 5.
    Hori, S., Takahashi, T., & Sakaguchi, S. (2003). Control of autoimmunity by naturally arising regulatory CD4+ T cells. Advances in Immunology, 81, 331–371.PubMedCrossRefGoogle Scholar
  6. 6.
    Reijonen, H., Mallone, R., Heninger, A. K., Laughlin, E. M., Kochik, S. A., Falk, B., Kwok, W. W., Greenbaum, C., & Nepom, G. T. (2004). GAD65-specific CD4+ T-cells with high antigen avidity are prevalent in peripheral blood of patients with type 1 diabetes. Diabetes, 53, 1987–1994.PubMedCrossRefGoogle Scholar
  7. 7.
    Baecher-Allan, C., Viglietta, V., & Hafler, D. A. (2004). Human CD4+CD25+ regulatory T cells. Seminars in Immunology, 16, 89–98.PubMedCrossRefGoogle Scholar
  8. 8.
    Atkinson, M. A., & Leiter, E. H. (1999). The NOD mouse model of type 1 diabetes: As good as it gets? Nature Medicine, 5, 601–604.PubMedCrossRefGoogle Scholar
  9. 9.
    Rapoport, M. J., Lazarus, A. H., Jaramillo, A., Speck, E., & Delovitch, T. L. (1993). Thymic T cell anergy in autoimmune nonobese diabetic mice is mediated by deficient T cell receptor regulation of the pathway of p21ras activation. Journal of Experimental Medicine, 177, 1221–1226.PubMedCrossRefGoogle Scholar
  10. 10.
    Gombert, J. M., Herbelin, A., Tancrede-Bohin, E., Dy, M., Carnaud, C., & Bach, J. F. (1996). Early quantitative and functional deficiency of NK1+-like thymocytes in the NOD mouse. European Journal of Immunology, 26, 2989–2998.PubMedCrossRefGoogle Scholar
  11. 11.
    King, C., Ilic, A., Koelsch, K., & Sarvetnick, N. (2004). Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell, 117, 265–277.PubMedCrossRefGoogle Scholar
  12. 12.
    Lederman, M. M., Ellner, J. J., & Rodman, H. M. (1981). Defective suppressor cell generation in juvenile onset diabetes. Journal of Immunology, 127, 2051–2055.Google Scholar
  13. 13.
    Asano, M., Toda, M., Sakaguchi, N., & Sakaguchi, S. (1996). Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. Journal of Experimental Medicine, 184, 387–396.PubMedCrossRefGoogle Scholar
  14. 14.
    Salomon, B., Lenschow, D. J., Rhee, L., Ashourian, N., Singh, B., Sharpe, A., & Bluestone, J. A. (2000). B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity, 12, 431–440.PubMedCrossRefGoogle Scholar
  15. 15.
    Wu, A. J., Hua, H., Munson, S. H., & McDevitt, H. O. (2002). Tumor necrosis factor-alpha regulation of CD4+CD25+ T cell levels in NOD mice. Proceedings of the National Academic Science USA, 99, 12287–12292.CrossRefGoogle Scholar
  16. 16.
    Liu, J., & Beller, D. (2002). Aberrant production of IL-12 by macrophages from several autoimmune-prone mouse strains is characterized by intrinsic and unique patterns of NF-kappa B expression and binding to the IL-12 p40 promoter. Journal of Immunology, 169, 581–586.Google Scholar
  17. 17.
    Serreze, D. V., Gaskins, H. R., & Leiter, E. H. (1993). Defects in the differentiation and function of antigen presenting cells in NOD/Lt mice. Journal of Immunology, 150, 2534–2543.Google Scholar
  18. 18.
    Alleva, D. G., Pavlovich, R. P., Grant, C., Kaser, S. B., & Beller, D. I. (2000). Aberrant macrophage cytokine production is a conserved feature among autoimmune-prone mouse strains: Elevated interleukin (IL)-12 and an imbalance in tumor necrosis factor-alpha and IL-10 define a unique cytokine profile in macrophages from young nonobese diabetic mice. Diabetes, 49, 1106–1115.PubMedCrossRefGoogle Scholar
  19. 19.
    Dahlen, E., Hedlund, G., & Dawe, K. (2000). Low CD86 expression in the nonobese diabetic mouse results in the impairment of both T cell activation and CTLA-4 up-regulation. Journal of Immunology, 164, 2444–2456.Google Scholar
  20. 20.
    Kukreja, A., Cost, G., Marker, J., Zhang, C., Sun, Z., Lin-Su, K., Ten, S., Sanz, M., Exley, M., Wilson, B., Porcelli, S., & Maclaren, N. (2002). Multiple immuno-regulatory defects in type-1 diabetes. Journal of Clinical Investigation, 109, 131–140.PubMedCrossRefGoogle Scholar
  21. 21.
    Weaver Jr., D. J., Poligone, B., Bui, T., Abdel-Motal, U. M., Baldwin Jr., A. S., & Tisch, R. (2001). Dendritic cells from nonobese diabetic mice exhibit a defect in NF-kappa B regulation due to a hyperactive I kappa B kinase. Journal of Immunology, 167, 1461–1468.Google Scholar
  22. 22.
    Yan, G., Shi, L., Penfornis, A., & Faustman, D. L. (2003). Impaired processing and presentation by MHC class II proteins in human diabetic cells. Journal of Immunology, 170, 620–627.Google Scholar
  23. 23.
    Atkinson, M. A., Kaufman, D. L., Campbell, L., Gibbs, K. A., Shah, S. C., Bu, D. F., Erlander, M. G., Tobin, A. J., & Maclaren, N. K. (1992). Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes. Lancet, 339, 458–459.PubMedCrossRefGoogle Scholar
  24. 24.
    Roep, B. O., Kallan, A. A., Duinkerken, G., Arden, S. D., Hutton, J. C., Bruining, G. J., & de Vries, R. R. (1995). T-cell reactivity to beta-cell membrane antigens associated with beta-cell destruction in IDDM. Diabetes, 44, 278–283.PubMedCrossRefGoogle Scholar
  25. 25.
    Atkinson, M. A., Bowman, M. A., Campbell, L., Darrow, B. L., Kaufman, D. L., & Maclaren, N. K. (1994). Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. Journal of Clinical Investigation, 94, 2125–2129.PubMedGoogle Scholar
  26. 26.
    Brooks-Worrell, B. M., Starkebaum, G. A., Greenbaum, C., & Palmer, J. P. (1996). Peripheral blood mononuclear cells of insulin-dependent diabetic patients respond to multiple islet cell proteins. Journal of Immunology, 157, 5668–5674.Google Scholar
  27. 27.
    Peakman, M., Stevens, E. J., Lohmann, T., Narendran, P., Dromey, J., Alexander, A., Tomlinson, A. J., Trucco, M., Gorga, J. C., & Chicz, R. M. (1999). Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4. Journal of Clinical Investigation, 104, 1449–1457.PubMedGoogle Scholar
  28. 28.
    Alleva, D. G., Crowe, P. D., Jin, L., Kwok, W. W., Ling, N., Gottschalk, M., Conlon, P. J., Gottlieb, P. A., Putnam, A. L., & Gaur, A. (2001). A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin. Journal of Clinical Investigation, 107, 173–180.PubMedGoogle Scholar
  29. 29.
    Viglietta, V., Kent, S. C., Orban, T., & Hafler, D. A. (2002). GAD65-reactive T cells are activated in patients with autoimmune type 1a diabetes. Journal of Clinical Investigation, 109, 895–903.PubMedCrossRefGoogle Scholar
  30. 30.
    Roep, B. O. (2003). The role of T-cells in the pathogenesis of type 1 diabetes: From cause to cure. Diabetologia, 46, 305–321.PubMedGoogle Scholar
  31. 31.
    Arif, S., Tree, T. I., Astill, T. P., Tremble, J. M., Bishop, A. J., Dayan, C. M., Roep, B. O., & Peakman, M. (2004). Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. Journal of Clinical Investigation, 113, 451–463.PubMedCrossRefGoogle Scholar
  32. 32.
    Tree, T. I., Duinkerken, G., Willemen, S., de Vries, R. R., & Roep, B. O. (2004). HLA-DQ-regulated T-cell responses to islet cell autoantigens insulin and GAD65. Diabetes, 53, 1692–1699.PubMedCrossRefGoogle Scholar
  33. 33.
    Chatenoud, L., Salomon, B., & Bluestone, J. A. (2001). Suppressor T cells—they’re back and critical for regulation of autoimmunity! Immunological Reviews, 182, 149–163.PubMedCrossRefGoogle Scholar
  34. 34.
    von Boehmer, H. (2005). Mechanisms of suppression by suppressor T cells. Nature Immunology, 6, 338–344.CrossRefGoogle Scholar
  35. 35.
    Sakaguchi, S. (2005). Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immunology, 6, 345–352.PubMedCrossRefGoogle Scholar
  36. 36.
    Sakaguchi, S. (2004). Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annual Review of Immunology, 22, 531–562.PubMedCrossRefGoogle Scholar
  37. 37.
    Takahashi, T., Kuniyasu, Y., Toda, M., Sakaguchi, N., Itoh, M., Iwata, M., Shimizu, J., & Sakaguchi, S. (1998). Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: Induction of autoimmune disease by breaking their anergic/suppressive state. International Immunology, 10, 1969–1980.PubMedCrossRefGoogle Scholar
  38. 38.
    Thornton, A. M., & Shevach, E. M. (2000). Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. Journal of Immunology, 164, 183–190.Google Scholar
  39. 39.
    Zola, H., Mantzioris, B. X., Webster, J., & Kette, F. E. (1989). Circulating human T and B lymphocytes express the p55 interleukin-2 receptor molecule (TAC, CD25). Immunology and Cell Biology, 67, 233–237.PubMedCrossRefGoogle Scholar
  40. 40.
    Bluestone, J. A. (1997). Is CTLA-4 a master switch for peripheral T cell tolerance? Journal of Immunology, 158, 1989–1993.Google Scholar
  41. 41.
    McHugh, R. S., Whitters, M. J., Piccirillo, C. A., Young, D. A., Shevach, E. M., Collins, M., & Byrne, M. C. (2002). CD4(+)CD25(+) immunoregulatory T cells: Gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity, 16, 311–323.PubMedCrossRefGoogle Scholar
  42. 42.
    Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y., & Sakaguchi, S. (2002). Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nature Immunology, 3, 135–142.PubMedCrossRefGoogle Scholar
  43. 43.
    Alyanakian, M. A., You, S., Damotte, D., Gouarin, C., Esling, A., Garcia, C., Havouis, S., Chatenoud, L., & Bach, J. F. (2003). Diversity of regulatory CD4+T cells controlling distinct organ-specific autoimmune diseases. Proceedings of the National Academic Science USA, 100, 15806–15811.CrossRefGoogle Scholar
  44. 44.
    Fu, S., Yopp, A. C., Mao, X., Chen, D., Zhang, N., Chen, D., Mao, M., Ding, Y., & Bromberg, J. S. (2004). CD4+ CD25+ CD62+ T-regulatory cell subset has optimal suppressive and proliferative potential. American Journal of Transplantation, 4, 65–78.PubMedCrossRefGoogle Scholar
  45. 45.
    Baecher-Allan, C., Brown, J. A., Freeman, G. J., & Hafler, D. A. (2001). CD4+CD25 high regulatory cells in human peripheral blood. Journal of Immunology, 167, 1245–1253.Google Scholar
  46. 46.
    Stephens, L. A., Mottet, C., Mason, D., & Powrie, F. (2001). Human CD4(+)CD25(+) thymocytes and peripheral T cells have immune suppressive activity in vitro. European Journal of Immunology, 31, 1247–1254.PubMedCrossRefGoogle Scholar
  47. 47.
    Thornton, A. M., & Shevach, E. M. (1998). CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. Journal of Experimental Medicine, 188, 287–296.PubMedCrossRefGoogle Scholar
  48. 48.
    Bhandoola, A., Tai, X., Eckhaus, M., Auchincloss, H., Mason, K., Rubin, S. A., Carbone, K. M., Grossman, Z., Rosenberg, A. S., & Singer, A. (2002). Peripheral expression of self-MHC-II influences the reactivity and self-tolerance of mature CD4(+) T cells: Evidence from a lymphopenic T cell model. Immunity, 17, 425–436.PubMedCrossRefGoogle Scholar
  49. 49.
    Hsieh, C. S., Liang, Y., Tyznik, A. J., Self, S. G., Liggitt, D., & Rudensky, A. Y. (2004). Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity, 21, 267–277.PubMedCrossRefGoogle Scholar
  50. 50.
    Suzuki, H., Kundig, T. M., Furlonger, C., Wakeham, A., Timms, E., Matsuyama, T., Schmits, R., Simard, J. J., Ohashi, P. S., & Griesser, H. (1995). Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science, 268, 1472–1476.PubMedCrossRefGoogle Scholar
  51. 51.
    Malek, T. R., Porter, B. O., Codias, E. K., Scibelli, P., & Yu, A. (2000). Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors. Journal of Immunology, 164, 2905–2914.Google Scholar
  52. 52.
    Wolf, M., Schimpl, A., & Hunig, T. (2001). Control of T cell hyperactivation in IL-2-deficient mice by CD4(+)CD25(-) and CD4(+)CD25(+) T cells: Evidence for two distinct regulatory mechanisms. European Journal of Immunology, 31, 1637–1645.PubMedCrossRefGoogle Scholar
  53. 53.
    Kagami, S., Nakajima, H., Suto, A., Hirose, K., Suzuki, K., Morita, S., Kato, I., Saito, Y., Kitamura, T., & Iwamoto, I. (2001). Stat5a regulates T helper cell differentiation by several distinct mechanisms. Blood, 97, 2358–2365.PubMedCrossRefGoogle Scholar
  54. 54.
    Takeda, I., Ine, S., Killeen, N., Ndhlovu, L. C., Murata, K., Satomi, S., Sugamura, K., & Ishii, N. (2004). Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. Journal of Immunology, 172, 3580–3589.Google Scholar
  55. 55.
    Kumanogoh, A., Wang, X., Lee, I., Watanabe, C., Kamanaka, M., Shi, W., Yoshida, K., Sato, T., Habu, S., Itoh, M., Sakaguchi, N., Sakaguchi, S., & Kikutani, H. (2001). Increased T cell autoreactivity in the absence of CD40–CD40 ligand interactions: A role of CD40 in regulatory T cell development. Journal of Immunology, 166, 353–360.Google Scholar
  56. 56.
    Scheffold, A., Huhn, J., & Hofer, T. (2005). Regulation of CD4(+)CD25(+) regulatory T cell activity: It takes (IL2) two to tango. European Journal of Immunology, 35, 1336–1341.PubMedCrossRefGoogle Scholar
  57. 57.
    Bayer, A. L., Yu, A., Adeegbe, D., & Malek, T. R. (2005). Essential role for interleukin-2 for CD4(+)CD25(+) T regulatory cell development during the neonatal period. Journal of Experimental Medicine, 201, 769–777.PubMedCrossRefGoogle Scholar
  58. 58.
    Setoguchi, R., Hori, S., Takahashi, T., & Sakaguchi, S. (2005). Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+ ) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. Journal of Experimental Medicine, 201, 723–735.PubMedCrossRefGoogle Scholar
  59. 59.
    Chen, W., Jin, W., Hardegen, N., Lei, K. J., Li, L., Marinos, N., McGrady, G., & Wahl, S. M. (2003). Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. Journal of Experimental Medicine, 198, 1875–1886.PubMedCrossRefGoogle Scholar
  60. 60.
    Goudy, K. S., Burkhardt, B. R., Wasserfall, C., Song, S., Campbell-Thompson, M. L., Brusko, T., Powers, M. A., Clare-Salzler, M. J., Sobel, E. S., Ellis, T. M., Flotte, T. R., & Atkinson, M. A. (2003). Systemic overexpression of IL-10 induces CD4+CD25+ cell populations in vivo and ameliorates type 1 diabetes in nonobese diabetic mice in a dose-dependent fashion. Journal of Immunology, 171, 2270–2278.Google Scholar
  61. 61.
    Nishibori, T., Tanabe, Y., Su, L., & David, M. (2004). Impaired development of CD4+ CD25+ regulatory T cells in the absence of STAT1: Increased susceptibility to autoimmune disease. Journal of Experimental Medicine, 199, 25–34.PubMedCrossRefGoogle Scholar
  62. 62.
    Caramalho, I., Lopes-Carvalho, T., Ostler, D., Zelenay, S., Haury, M., & Demengeot, J. (2003). Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. Journal of Experimental Medicine, 197, 403–411.PubMedCrossRefGoogle Scholar
  63. 63.
    Fehervari, Z., & Sakaguchi, S. (2004). Control of Foxp3+ CD25+CD4+ regulatory cell activation and function by dendritic cells. International Immunology, 16, 1769–1780.PubMedCrossRefGoogle Scholar
  64. 64.
    Jiang, S., Game, D. S., Davies, D., Lombardi, G., & Lechler, R. I. (2005). Activated CD1d-restricted natural killer T cells secrete IL-2: Innate help for CD4+CD25+ regulatory T cells? European Journal of Immunology, 35, 1193–1200.PubMedCrossRefGoogle Scholar
  65. 65.
    Fontenot, J. D., & Rudensky, A. Y. (2004). Molecular aspects of regulatory T cell development. Seminars in Immunology, 16, 73–80.PubMedCrossRefGoogle Scholar
  66. 66.
    Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J. L., Buist, N., Levy-Lahad, E., Mazzella, M., Goulet, O., Perroni, L., Bricarelli, F. D., Byrne, G., McEuen, M., Proll, S., Appleby, M., & Brunlow, M. E. (2001). X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature Genetics, 27, 18–20.PubMedCrossRefGoogle Scholar
  67. 67.
    Wildin, R. S., Smyk-Pearson, S., & Filipovich, A. H. (2002). Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. Journal of Medical Genetics, 39, 537–545.PubMedCrossRefGoogle Scholar
  68. 68.
    Smyk-Pearson, S. K., Bakke, A. C., Held, P. K., & Wildin, R. S. (2003). Rescue of the autoimmune scurfy mouse by partial bone marrow transplantation or by injection with T-enriched splenocytes. Clinical and Experimental Immunology, 133, 193–199.PubMedCrossRefGoogle Scholar
  69. 69.
    Sadlack, B., Merz, H., Schorle, H., Schimpl, A., Feller, A. C., & Horak, I. (1993). Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell, 75, 253–261.PubMedCrossRefGoogle Scholar
  70. 70.
    Willerford, D. M., Chen, J., Ferry, J. A., Davidson, L., Ma, A., & Alt, F. W. (1995). Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity, 3, 521–530.PubMedCrossRefGoogle Scholar
  71. 71.
    Suzuki, H., Zhou, Y. W., Kato, M., Mak, T. W., & Nakashima, I. (1999). Normal regulatory alpha/beta T cells effectively eliminate abnormally activated T cells lacking the interleukin 2 receptor beta in vivo. Journal of Experimental Medicine, 190, 1561–1572.PubMedCrossRefGoogle Scholar
  72. 72.
    Leveen, P., Larsson, J., Ehinger, M., Cilio, C. M., Sundler, M., Sjostrand, L. J., Holmdahl, R., & Karlsson, S. (2002). Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood, 100, 560–568.PubMedCrossRefGoogle Scholar
  73. 73.
    Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H., & Mak, T. W. (1995). Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science, 270, 985–988.PubMedCrossRefGoogle Scholar
  74. 74.
    Bennett, C. L., Christie, J., Ramsdell, F., Brunkow, M. E., Ferguson, P. J., Whitesell, L., Kelly, T. E., Saulsbury, F. T., Chance, P. F., & Ochs, H. D. (2001). The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nature Genetics, 27, 20–21.PubMedCrossRefGoogle Scholar
  75. 75.
    Khattri, R., Kasprowicz, D., Cox, T., Mortrud, M., Appleby, M. W., Brunkow, M. E., Ziegler, S. F., & Ramsdell, F. (2001). The amount of scurfin protein determines peripheral T cell number and responsiveness. Journal of Immunology, 167, 6312–6320.Google Scholar
  76. 76.
    Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003). Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunology, 4, 330–336.PubMedCrossRefGoogle Scholar
  77. 77.
    Hori, S., Nomura, T., & Sakaguchi, S. (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science, 299, 1057–1061.PubMedCrossRefGoogle Scholar
  78. 78.
    Schubert, L. A., Jeffery, E., Zhang, Y., Ramsdell, F., & Ziegler, S. F. (2001). Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. Journal of Biological Chemistry, 276, 37672–37679.PubMedCrossRefGoogle Scholar
  79. 79.
    Lehmann, O. J., Sowden, J. C., Carlsson, P., Jordan, T., & Bhattacharya, S. S. (2003). Fox’s in development and disease. Trends Genetics, 19, 339–344.CrossRefGoogle Scholar
  80. 80.
    Horwitz, D. A., Zheng, S. G., & Gray, J. D. (2003). The role of the combination of IL-2 and TGF-beta or IL-10 in the generation and function of CD4+ CD25+ and CD8+ regulatory T cell subsets. Journal of Leukocyte Biology, 74, 471–478.PubMedCrossRefGoogle Scholar
  81. 81.
    Nakamura, K., Kitani, A., & Strober, W. (2001). Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. Journal of Experimental Medicine, 194, 629–644.PubMedCrossRefGoogle Scholar
  82. 82.
    Piccirillo, C. A., Letterio, J. J., Thornton, A. M., McHugh, R. S., Mamura, M., Mizuhara, H., & Shevach, E. M. (2002). CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. Journal of Experimental Medicine, 196, 237–246.PubMedCrossRefGoogle Scholar
  83. 83.
    Walker, M. R., Kasprowicz, D. J., Gersuk, V. H., Benard, A., Van Landeghen, M., Buckner, J. H., & Ziegler, S. F. (2003). Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+. Journal of Clinical Investigation, 112, 1437–1443.PubMedCrossRefGoogle Scholar
  84. 84.
    Huber, S., Schramm, C., Lehr, H. A., Mann, A., Schmitt, S., Becker, C., Protschka, M., Galle, P. R., Neurath, M. F., & Blessing, M. (2004). TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. Journal of Immunology, 173, 6526–6531.Google Scholar
  85. 85.
    Fahlen, L., Read, S., Gorelik, L., Hurst, S. D., Coffman, R. L., Flavell, R. A., & Powrie, F. (2005). T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. Journal of Experimental Medicine, 201, 737–746.PubMedCrossRefGoogle Scholar
  86. 86.
    Marie, J. C., Letterio, J. J., Gavin, M., & Rudensky, A. Y. (2005). TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. Journal of Experimental Medicine, 201, 1061–1067.PubMedCrossRefGoogle Scholar
  87. 87.
    Morgan, M. E., van Bilsen, J. H., Bakker, A. M., Heemskerk, B., Schilham, M. W., Hartgers, F. C., Elferink, B. G., van der Zanden, L, de Vries, R. R., Huizinga, T. W., Ottenhoff, T. H., & Toes, R. E. (2005). Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Human Immunology, 66, 13–20.PubMedCrossRefGoogle Scholar
  88. 88.
    Jaeckel, E., von Boehmer, H., & Manns, M. P. (2005). Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes, 54, 306–310.PubMedCrossRefGoogle Scholar
  89. 89.
    Grewal, I. S., Grewal, K. D., Wong, F. S., Wang, H., Picarella, D. E., Janeway Jr., C. A. , & Flavell, R. A. (2002). Expression of transgene encoded TGF-beta in islets prevents autoimmune diabetes in NOD mice by a local mechanism. Journal of Autoimmunology, 19, 9–22.CrossRefGoogle Scholar
  90. 90.
    Pop, S. M., Wong, C. P., Culton, D. A., Clarke, S. H., & Tisch, R. (2005). Single cell analysis shows decreasing FoxP3 and TGFbeta1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes. Journal of Experimental Medicine, 201, 1333–1346.PubMedCrossRefGoogle Scholar
  91. 91.
    You, S., Belghith, M., Cobbold, S., Alyanakian, M. A., Gouarin, C., Barriot, S., Garcia, C., Waldmann, H., Bach, J. F., & Chatenoud, L. (2005). Autoimmune diabetes onset results from qualitative rather than quantitative age dependent changes in pathogenic T-cells. Diabetes, 54, 1415–1422.PubMedCrossRefGoogle Scholar
  92. 92.
    Viglietta, V., Baecher-Allan, C., Weiner, H. L., & Hafler, D. A. (2004). Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. Journal of Experimental Medicine, 199, 971–979.PubMedCrossRefGoogle Scholar
  93. 93.
    Kriegel, M. A., Lohmann, T., Gabler, C., Blank, N., Kalden, J. R., & Lorenz, H. M. (2004). Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome Type II. Journal of Experimental Medicine, 199, 1285–1291.PubMedCrossRefGoogle Scholar
  94. 94.
    Liu, M. F., Wang, C. R., Fung, L. L., & Wu, C. R. (2004). Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scandinavian Journal of Immunology, 59, 198–202.PubMedCrossRefGoogle Scholar
  95. 95.
    Lindley, S., Dayan, C. M., Bishop, A., Roep, B. O., Peakman, M., & Tree, T. I. (2005). Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes, 54, 92–99.PubMedCrossRefGoogle Scholar
  96. 96.
    Putnam, A. L., Vendrame, F., Dotta, F., & Gottlieb, P. A. (2005). CD4+CD25 high regulatory T cells in human autoimmune diabetes. Journal of Autoimmunology, 24, 55–62.CrossRefGoogle Scholar
  97. 97.
    Brusko, T. M., Wasserfall, C. H., Clare-Salzler, M. J., Schatz, D. A., & Atkinson, M. A. (2005). Functional defects and the influence of age on the frequency of CD4+CD25+ T-cells in type 1 diabetes. Diabetes, 54, 1407–1414.PubMedCrossRefGoogle Scholar
  98. 98.
    Zavattari, P., Deidda, E., Pitzalis, M., Zoa, B., Moi, L., Lampis, R., Contu, D., Motzo, C., Frogia, P., Angius, E., Maioli, M., Todd, J. A., & Cucca, F. (2004). No association between variation of the FOXP3 gene and common type 1 diabetes in the Sardinian population. Diabetes, 53, 1911–1914.PubMedCrossRefGoogle Scholar
  99. 99.
    Vella, A., Cooper, J. D., Lowe, C. E., Walker, N., Nutland, S., Widmer, B., Jones, R., Ring, S. M., McArdle, W., Pembrey, M. E., Strachan, D. P., Dunger, D. B., Twells, R. C., Clayton, D. G., & Todd, J. A. (2005). Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. American Journal of Human Genetics, 76, 773–779.PubMedCrossRefGoogle Scholar
  100. 100.
    Baecher-Allan, C., Wolf, E., & Hafler, D. A. (2005). Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4(+)CD25(+) T cells. Clinical Immunology, 115, 10–18.PubMedCrossRefGoogle Scholar
  101. 101.
    Earle, K. E., Tang, Q., Zhou, X., Liu, W., Zhu, S., Bonyhadi, M. L., & Bluestone, J. A. (2005). In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation. Clinical Immunology, 115, 3–9.PubMedCrossRefGoogle Scholar
  102. 102.
    Brusko, T., Wasserfall, C., McGrail, K., Schatz, R., Viener, H. L., Schatz, D., Haller, M., Rockell, J., Gottlieb, P., Clare-Salzler, M., & Atkinson, M. (2007). No Alterations in the Frequency of FOXP3+ Regulatory T-Cells in Type 1 Diabetes. Diabetes, 56(3), 604–612.PubMedCrossRefGoogle Scholar
  103. 103.
    Liu, W., Putnam, A. L., Xu-Yu, Z., Szot, G. L., Lee, M. R., Zhu, S., Gottlieb, P. A., Kapranov, P., Gingeras, T. R., Fazekas de St Groth, B., Clayberger, C., Soper, D. M., Ziegler, S. F., & Bluestone, J. A. (2006). CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. Journal of Experimental Medicine, 203(7), 1701–1711.PubMedCrossRefGoogle Scholar
  104. 104.
    Battaglia, M., Stabilini, A., Migliavacca, B., Horejs-Hoeck, J., Kaupper, T., & Roncarolo, M. G. (2006). Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. Journal of Immunology, 177(12), 8338–8347.Google Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Department of Pathology, Immunology and Laboratory MedicineUniversity of FloridaGainesvilleUSA

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