Exploiting the potential of regulatory T cells in the control of type 1 diabetes

  • Nadia Giarratana
  • Giuseppe Penna
  • Silvia Gregori
  • Kenn C. Daniel
  • Luciano Adorini
Part of the Progress in Inflammation Research book series (PIR)


Autoimmune Diabetes Nonobese Diabetic Mouse Human Islet Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kikutani H, Makino S (1992) The murine autoimmune diabetes model: NOD and related strains. Adv Immunol 51: 285–322PubMedGoogle Scholar
  2. 2.
    Atkinson MA, Leiter EH (1999) The NOD mouse model of type 1 diabetes: as good as it gets? Nat Med 5: 601–604PubMedGoogle Scholar
  3. 3.
    Adorini L, Gregori S, Harrison LC (2002) Understanding autoimmune diabetes: insights from mouse models. Trends Mol Med 8: 31–38PubMedGoogle Scholar
  4. 4.
    Trembleau S, Penna G, Bosi E, Mortara A, Gately MK, Adorini L (1995) IL-12 administration induces Th1 cells and accelerates autoimmune diabetes in NOD mice. J Exp Med 181: 817–821PubMedGoogle Scholar
  5. 5.
    Benoist C, Mathis D (1997) Cell death mediators in autoimmune diabetes — no shortage of suspects. Cell 89: 1–3PubMedGoogle Scholar
  6. 6.
    Delovitch TL, Singh B (1997) The non-obese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7: 727–738PubMedGoogle Scholar
  7. 7.
    Ridgway WM, Fasso M, Lanctot A, Garvey C, Fathman CG (1996) Breaking self-tolerance in nonobese diabetic mice. J Exp Med 183: 1657–1662PubMedGoogle Scholar
  8. 8.
    Ymer SI, Huang D, Penna G, Gregori S, Branson K, Adorini L, Morahan G (2002) Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains. Genes Immun 3: 151–157PubMedGoogle Scholar
  9. 9.
    Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12: 431–440PubMedGoogle Scholar
  10. 10.
    Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2: 389–400PubMedGoogle Scholar
  11. 11.
    Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101: 455–458PubMedGoogle Scholar
  12. 12.
    Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 1057–1061PubMedGoogle Scholar
  13. 13.
    Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4: 330–336PubMedGoogle Scholar
  14. 14.
    Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4: 337–342PubMedGoogle Scholar
  15. 15.
    Read S, Malmstrom V, Powrie F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192: 295–302PubMedGoogle Scholar
  16. 16.
    Stephens LA, Mason D (2000) CD25 is a marker for CD4+ thymocytes that prevent autoimmune diabetes in rats, but peripheral T cells with this function are found in both CD25+ and CD25 subpopulations. J Immunol 165: 3105–3110PubMedGoogle Scholar
  17. 17.
    Wu AJ, Hua H, Munson SH, McDevitt HO (2002) Tumor necrosis factor-alpha regulation of CD4+CD25+ T cell levels in NOD mice. Proc Natl Acad Sci USA 99: 12287–12292PubMedGoogle Scholar
  18. 18.
    Gregori S, Giarratana N, Smiroldo S, Adorini L (2003) Dynamics of pathogenic and suppressor T cells in autoimmune diabetes development. J Immunol 171: 4040–4047PubMedGoogle Scholar
  19. 19.
    Herman AE, Freeman GJ, Mathis D, Benoist C (2004) CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med 199: 1479–1489PubMedGoogle Scholar
  20. 20.
    Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K, Ten S, Sanz M, Exley M, Wilson B et al. (2002) Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 109: 131–140PubMedGoogle Scholar
  21. 21.
    Arif S, Tree TI, Astill TP, Tremble JM, Bishop AJ, Dayan CM, Roep BO, Peakman M (2004) Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest 113: 451–463PubMedGoogle Scholar
  22. 22.
    Szanya V, Ermann J, Taylor C, Holness C, Fathman CG (2002) The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. J Immunol 169: 2461–2465PubMedGoogle Scholar
  23. 23.
    Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA (2004) In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199: 1455–1465PubMedGoogle Scholar
  24. 24.
    Horwitz DA, Zheng SG, Gray JD, Wang JH, Ohtsuka K, Yamagiwa S (2004) Regulatory T cells generated ex vivo as an approach for the therapy of autoimmune disease. Semin Immunol 16: 135–143Google Scholar
  25. 25.
    Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA (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: 5213–5221PubMedGoogle Scholar
  26. 26.
    Yamazaki S, Iyoda T, Tarbell K, Olson K, Velinzon K, Inaba K, Steinman RM (2003) Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med 198: 235–247PubMedGoogle Scholar
  27. 27.
    Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM (2004) CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 199: 1467–1477PubMedGoogle Scholar
  28. 28.
    Lin CH, Hunig T (2003) Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist. Eur J Immunol 33: 626–638PubMedGoogle Scholar
  29. 29.
    Chatenoud L (2003) CD3-specific antibody-induced active tolerance: from bench to bedside. Nat Rev Immunol 3: 123–132PubMedGoogle Scholar
  30. 30.
    Chatenoud L, Thervet E, Primo J, Bach JF (1994) Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA 91: 123–127PubMedGoogle Scholar
  31. 31.
    Chatenoud L, Primo J, Bach JF (1997) CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol 158: 2947–2954PubMedGoogle Scholar
  32. 32.
    von Herrath MG, Coon B, Wolfe T, Chatenoud L (2002) Nonmitogenic CD3 antibody reverses virally induced (rat insulin promoter-lymphocytic choriomeningitis virus) autoimmune diabetes without impeding viral clearance. J Immunol 168: 933–941PubMedGoogle Scholar
  33. 33.
    Belghith M, Bluestone JA, Barriot S, Megret J, Bach JF, Chatenoud L (2003) TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 9: 1202–1208PubMedGoogle Scholar
  34. 34.
    Peng Y, Laouar Y, Li MO, Green EA, Flavell RA (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: 4572–4577PubMedGoogle Scholar
  35. 35.
    Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan DM, Xu D, Zivin RA, Bluestone JA (2002) Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346: 1692–1698PubMedGoogle Scholar
  36. 36.
    Herold KC, Burton JB, Francois F, Poumian-Ruiz E, Glandt M, Bluestone JA (2003) Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3gamma1(Ala-Ala). J Clin Invest 111: 409–418PubMedGoogle Scholar
  37. 37.
    Bolt S, Routledge E, Lloyd I, Chatenoud L, Pope H, Gorman SD, Clark M, Waldmann H (1993) The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur J Immunol 23: 403–411PubMedGoogle Scholar
  38. 38.
    Alegre ML, Peterson LJ, Xu D, Sattar HA, Jeyarajah DR, Kowalkowski K, Thistlethwaite JR, Zivin RA, Jolliffe L, Bluestone JA (1994) A non-activating “humanized” anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Transplantation 57: 1537–1543PubMedGoogle Scholar
  39. 39.
    Hering BJ, Kandaswamy R, Harmon JV, Ansite JD, Clemmings SM, Sakai T, Paraskevas S, Eckman PM, Sageshima J, Nakano M et al (2004) Transplantation of cultured islets from two-layer preserved pancreases in type 1 diabetes with anti-CD3 antibody. Am J Transplant 4: 390–401PubMedGoogle Scholar
  40. 40.
    Adorini L, Giarratana N, Penna G (2004) Pharmacological induction of tolerogenic dendritic cells and regulatory T cells. Semin Immunol 16: 127–134PubMedGoogle Scholar
  41. 41.
    Deluca HF, Cantorna MT (2001) Vitamin D: its role and uses in immunology. FASEB J 15: 2579–2585PubMedGoogle Scholar
  42. 42.
    Mathieu C, Adorini L (2002) The coming of age of 1,25-dihydroxyvitamin D(3) analogs as immunomodulatory agents. Trends Mol Med 8: 174–179PubMedGoogle Scholar
  43. 43.
    Adorini L (2002) Immunomodulatory effects of vitamin D receptor ligands in autoimmune diseases. Int Immunopharmacol 2: 1017–1028PubMedGoogle Scholar
  44. 44.
    Adorini L (2002) 1,25-Dihydroxyvitamin D3 analogs as potential therapies in transplantation. Curr Opin Invest Drugs 3: 1458–1463Google Scholar
  45. 45.
    Griffin MD, Xing N, Kumar R (2003) Vitamin D and its analogs as regulators of immune activation and antigen presentation. Annu Rev Nutr 23: 117–145PubMedGoogle Scholar
  46. 46.
    Carlberg C, Polly P (1998) Gene regulation by vitamin D3. Crit Rev Eukaryot Gene Expr 8: 19–42PubMedGoogle Scholar
  47. 47.
    Penna G, Adorini L (2000) 1,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 164: 2405–2411PubMedGoogle Scholar
  48. 48.
    Piemonti L, Monti P, Sironi M, Fraticelli P, Leone BE, Dal Cin E, Allavena P, Di Carlo V (2000) Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol 164: 4443–4451PubMedGoogle Scholar
  49. 49.
    Griffin MD, Lutz WH, Phan VA, Bachman LA, McKean DJ, Kumar R (2000) Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem Biophys Res Commun 270: 701–708PubMedGoogle Scholar
  50. 50.
    Berer A, Stockl J, Majdic O, Wagner T, Kollars M, Lechner K, Geissler K, Oehler L (2000) 1,25-Dihydroxyvitamin D(3) inhibits dendritic cell differentiation and maturation in vitro. Exp Hematol 28: 575–583PubMedGoogle Scholar
  51. 51.
    Canning MO, Grotenhuis K, de Wit H, Ruwhof C, Drexhage HA (2001) 1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes. Eur J Endocrinol 145: 351–357PubMedGoogle Scholar
  52. 52.
    van Halteren AG, van Etten E, de Jong EC, Bouillon R, Roep BO, Mathieu C (2002) Redirection of human autoreactive T-cells Upon interaction with dendritic cells modulated by TX527, an analog of 1,25 dihydroxyvitamin D(3). Diabetes 51: 2119–2125PubMedGoogle Scholar
  53. 53.
    Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG, Kilby MD, Moss PA, Chakraverty R (2003) Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 170: 5382–5390PubMedGoogle Scholar
  54. 54.
    Griffin MD, Lutz W, Phan VA, Bachman LA, McKean DJ, Kumar R (2001) Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: A vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci USA 98: 6800–6805PubMedGoogle Scholar
  55. 55.
    Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O’Garra A (2001) 1alpha,25-Dihydroxyvitamin D3 has a direct effect on naive CD4+ T Cells to Enhance the Development of Th2 Cells. J Immunol 167: 4974–4980PubMedGoogle Scholar
  56. 56.
    Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF, de Waal-Malefyt R, Coffman RL, Hawrylowicz CM, O’Garra A (2002)In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)-and Th2-inducing cytokines. J Exp Med 195: 603–616PubMedGoogle Scholar
  57. 57.
    Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A, Barthlott T, Stockinger B, Wraith DC, O’Garra A (2004) IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol 172: 5986–5993PubMedGoogle Scholar
  58. 58.
    Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L (2001) Regulatory T cells induced by 1α,25-Dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol 167: 1945–1953PubMedGoogle Scholar
  59. 59.
    Mehling A, Grabbe S, Voskort M, Schwarz T, Luger TA, Beissert S (2000) Mycopheno-late mofetil impairs the maturation and function of murine dendritic cells. J Immunol 165: 2374–2381PubMedGoogle Scholar
  60. 60.
    Gregori G, Giarratana N, Smiroldo S, Uskokovic M, Adorini L (2002) A 1α,25-Dihydroxyvitamin D3 analog enhances regulatory T cells and arrests autoimmune diabetes in NOD mice. Diabetes 51: 1367–1374PubMedGoogle Scholar
  61. 61.
    Giarratana N, Penna G, Amuchastegui S, Mariani R, Daniel KC, Adorini L (2004) A vitamin D analog downregulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development. J Immunol 173: 2280–2287PubMedGoogle Scholar
  62. 62.
    Rossi D, Zlotnik A (2000) The biology of chemokines and their receptors. Annu Rev Immunol 18: 217–242PubMedGoogle Scholar
  63. 63.
    Shimada A, Morimoto J, Kodama K, Suzuki R, Oikawa Y, Funae O, Kasuga A, Saruta T, Narumi S (2001) Elevated serum IP-10 levels observed in type 1 diabetes. Diabetes Care 24: 510–515PubMedGoogle Scholar
  64. 64.
    Nicoletti F, Conget I, Di Mauro M, Di Marco R, Mazzarino MC, Bendtzen K, Messina A, Gomis R (2002) Serum concentrations of the interferon-gamma-inducible chemokine IP-10/CXCL10 are augmented in both newly diagnosed Type I diabetes mellitus patients and subjects at risk of developing the disease. Diabetologia 45: 1107–1110PubMedGoogle Scholar
  65. 65.
    Piemonti L, Leone BE, Nano R, Saccani A, Monti P, Maffi P, Bianchi G, Sica A, Peri G, Melzi R et al. (2002) Human pancreatic islets produce and secrete MCP-1/CCL2: relevance in human islet transplantation. Diabetes 51: 55–65PubMedGoogle Scholar
  66. 66.
    Xie JH, Nomura N, Lu M, Chen SL, Koch GE, Weng Y, Rosa R, Di Salvo J, Mudgett J, Peterson LB et al. JA (2003) Antibody-mediated blockade of the CXCR3 chemokine receptor results in diminished recruitment of T helper 1 cells into sites of inflammation. J Leukoc Biol 73: 771–780PubMedGoogle Scholar
  67. 67.
    Frigerio S, Junt T, Lu B, Gerard C, Zumsteg U, Hollander GA, Piali L (2002) Beta cells are responsible for CXCR3-mediated T-cell infiltration in insulitis. Nat Med 8: 1414–1420PubMedGoogle Scholar
  68. 68.
    D’Ambrosio D, Sinigaglia F, Adorini L (2003) Special attractions for suppressor T cells. Trends Immunol 24: 122–126PubMedGoogle Scholar
  69. 69.
    Penna G, Vulcano M, Roncari A, Facchetti F, Sozzani S, Adorini L (2002) Differential chemokine production by myeloid and plasmacytoid dendritic cells. J Immunol 169: 6673–6676PubMedGoogle Scholar
  70. 70.
    Shortman K, Liu YJ (2002) Mouse and human dendritic cell subtypes. Nat Rev Immunol 2: 151–161PubMedGoogle Scholar
  71. 71.
    Bystry RS, Aluvihare V, Welch KA, Kallikourdis M, Betz AG (2001) B cells and professional APCs recruit regulatory T cells via CCL4. Nat Immunol 2: 1126–1132PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2005

Authors and Affiliations

  • Nadia Giarratana
    • 1
  • Giuseppe Penna
    • 1
  • Silvia Gregori
    • 1
  • Kenn C. Daniel
    • 1
  • Luciano Adorini
    • 1
  1. 1.BioXellMilanoItaly

Personalised recommendations