Current Diabetes Reports

, Volume 8, Issue 2, pp 101–106 | Cite as

T cells in the pathogenesis of type 1 diabetes

Article

Abstract

T lymphocytes’ crucial role in the autoimmune process leading to insulin-dependent type 1 diabetes is now universally recognized. Research focuses on identifying pathogenic and nonpathogenic T cells, understanding how they are primed and expanded, characterizing their antigen specificity, and ultimately on devising strategies to blunt their autoaggressive action. In this review, we focus on recent progress identified in three different areas. Results obtained with transgenic mice acknowledge proinsulin’s unique role in triggering autoimmunity and suggest that other β-cell proteins are recognized as a result of epitope spreading, at least in the nonobese diabetic mouse. Progress has also been achieved by developing and validating reliable CD4+ and CD8+ T-cell tests that may prove valuable for diagnostic and prognostic purposes in the near future. Finally, recent results provide novel and important guidance for manipulating autoreactive T-cell responses against β-cell antigens.

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References and Recommended Reading

  1. 1.
    Bottazzo GF, Florin-Christensen A, Doniach D: Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 1974, 2:1279–1283.PubMedCrossRefGoogle Scholar
  2. 2.
    Reijonen H, Daniels TL, Lernmark A, Nepom GT: GAD65-specific autoantibodies enhance the presentation of an immunodominant T-cell epitope from GAD65. Diabetes 2000, 49:1621–1626.PubMedCrossRefGoogle Scholar
  3. 3.
    Martin S, Wolf-Eichbaum D, Duinkerken G, et al.: Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency. N Engl J Med 2001, 345:1036–1040.PubMedCrossRefGoogle Scholar
  4. 4.
    Haskins K, Wegmann D: Diabetogenic T-cell clones. Diabetes 1996, 45:1299–1305.PubMedCrossRefGoogle Scholar
  5. 5.
    Katz J, Benoist C, Mathis D: Major histocompatibility complex class I molecules are required for the development of insulitis in non-obese diabetic mice. Eur J Immunol 1993, 23:3358–3360.PubMedCrossRefGoogle Scholar
  6. 6.
    Serreze DV, Leiter EH, Christianson GJ, et al.: Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant. Diabetes 1994, 43:505–509.PubMedCrossRefGoogle Scholar
  7. 7.
    Wicker LS, Leiter EH, Todd JA, et al.: Beta 2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Diabetes 1994, 43:500–504.PubMedCrossRefGoogle Scholar
  8. 8.
    Wang B, Gonzalez A, Benoist C, Mathis D: The role of CD8+ T cells in the initiation of insulin-dependent diabetes mellitus. Eur J Immunol 1996, 26:1762–1769.PubMedCrossRefGoogle Scholar
  9. 9.
    Wong FS, Karttunen J, Dumont C, et al.: Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library. Nat Med 1999, 5:1026–1031.PubMedCrossRefGoogle Scholar
  10. 10.
    Amrani A, Verdaguer J, Serra P, et al.: Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature 2000, 406:739–742.PubMedCrossRefGoogle Scholar
  11. 11.
    DiLorenzo TP, Serreze DV: The good turned ugly: immunopathogenic basis for diabetogenic CD8+ T cells in NOD mice. Immunol Rev 2005, 204:250–263.PubMedCrossRefGoogle Scholar
  12. 12.
    Walter U, Santamaria P: CD8+ T cells in autoimmunity. Curr Opin Immunol 2005, 17:624–631.PubMedCrossRefGoogle Scholar
  13. 13.
    Bendelac A, Carnaud C, Boitard C, Bach JF: Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. J Exp Med 1987, 166:823–832.PubMedCrossRefGoogle Scholar
  14. 14.
    Nagata M, Santamaria P, Kawamura T, et al.: Evidence for the role of CD8+ cytotoxic T cells in the destruction of pancreatic beta-cells in nonobese diabetic mice. J Immunol 1994, 152:2042–2050.PubMedGoogle Scholar
  15. 15.
    Serreze DV, Chapman HD, Varnum DS, et al.: Initiation of autoimmune diabetes in NOD/Lt mice is MHC class I-dependent. J Immunol 1997, 158:3978–3986.PubMedGoogle Scholar
  16. 16.
    Graser RT, DiLorenzo TP, Wang F, et al.: Identification of a CD8 T cell that can independently mediate autoimmune diabetes development in the complete absence of CD4 T cell helper functions. J Immunol 2000, 164:3913–3918.PubMedGoogle Scholar
  17. 17.
    Daniel D, Gill RG, Schloot N, Wegmann D: Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Eur J Immunol 1995, 25:1056–1062.PubMedCrossRefGoogle Scholar
  18. 18.
    Thebault-Baumont K, Dubois-Laforgue D, Krief P, et al.: Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J Clin Invest 2003, 111:851–857.PubMedGoogle Scholar
  19. 19.
    French MB, Allison J, Cram DS, et al.: Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice. Diabetes 1997, 46:34–39.PubMedCrossRefGoogle Scholar
  20. 20.
    Moriyama H, Abiru N, Paronen J, et al.: Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse. Proc Natl Acad Sci U S A 2003, 100:10376–10381.PubMedCrossRefGoogle Scholar
  21. 21.
    Nakayama M, Abiru N, Moriyama H, et al.: Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005, 435:220–223.PubMedCrossRefGoogle Scholar
  22. 22.
    Nakayama M, Beilke JN, Jasinski JM, et al.: Priming and effector dependence on insulin B:9–23 peptide in NOD islet autoimmunity. J Clin Invest 2007, 117:1835–1843.PubMedCrossRefGoogle Scholar
  23. 23.
    Krishnamurthy B, Dudek NL, McKenzie MD, et al.: Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. J Clin Invest 2006, 116:3258–3265.PubMedCrossRefGoogle Scholar
  24. 24.
    Lieberman SM, Takaki T, Han B, et al.: Individual nonobese diabetic mice exhibit unique patterns of CD8+ T cell reactivity to three islet antigens, including the newly identified widely expressed dystrophia myotonica kinase. J Immunol 2004, 173:6727–6734.PubMedGoogle Scholar
  25. 25.
    Kubosaki A, Gross S, Miura J, et al.: Targeted disruption of the IA-2beta gene causes glucose intolerance and impairs insulin secretion but does not prevent the development of diabetes in NOD mice. Diabetes 2004, 53:1684–1691.PubMedCrossRefGoogle Scholar
  26. 26.
    Jaeckel E, Klein L, Martin-Orozco N, von Boehmer H: Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase. J Exp Med 2003, 197:1635–1644.PubMedCrossRefGoogle Scholar
  27. 27.
    Jaeckel E, Lipes MA, von Boehmer H: Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. Nat Immunol 2004, 5:1028–1035.PubMedCrossRefGoogle Scholar
  28. 28.
    Han B, Serra P, Amrani A, et al.: Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low-affinity peptide. Nat Med 2005, 11:645–652.PubMedCrossRefGoogle Scholar
  29. 29.
    Bielekova B, Goodwin B, Richert N, et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat Med 2000, 6:1167–1175.PubMedCrossRefGoogle Scholar
  30. 30.
    Kappos L, Comi G, Panitch H, et al.: Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. The Altered Peptide Ligand in Relapsing MS Study Group. Nat Med 2000, 6:1176–1182.PubMedCrossRefGoogle Scholar
  31. 31.
    Thomas HE, Darwiche R, Corbett JA, Kay TW: Evidence that beta cell death in the nonobese diabetic mouse is Fas independent. J Immunol 1999, 163:1562–1569.PubMedGoogle Scholar
  32. 32.
    Yamada K, Takane-Gyotoku N, Yuan X, et al.: Mouse islet cell lysis mediated by interleukin-1-induced Fas. Diabetologia 1996, 39:1306–1312.PubMedCrossRefGoogle Scholar
  33. 33.
    Amrani A, Verdaguer J, Thiessen S, et al.: IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. J Clin Invest 2000, 105:459–468.PubMedCrossRefGoogle Scholar
  34. 34.
    Perez-Diez A, Joncker NT, Choi K, et al.: CD4 cells can be more efficient at tumor rejection than CD8 cells. Blood 2007, 109:5346–5354.PubMedCrossRefGoogle Scholar
  35. 35.
    Allison J, Thomas HE, Catterall T, et al.: Transgenic expression of dominant-negative Fas-associated death domain protein in beta cells protects against Fas ligand-induced apoptosis and reduces spontaneous diabetes in nonobese diabetic mice. J Immunol 2005, 175:293–301.PubMedGoogle Scholar
  36. 36.
    Kagi D, Odermatt B, Seiler P, et al.: Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. J Exp Med 1997, 186:989–997.PubMedCrossRefGoogle Scholar
  37. 37.
    Bottazzo GF, Dean BM, McNally JM, et al.: In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med 1985, 313:353–360.PubMedGoogle Scholar
  38. 38.
    Arif S, Tree TI, Astill TP, et al.: Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest 2004, 113:451–463.PubMedGoogle Scholar
  39. 39.
    Mallone R, Martinuzzi E, Blancou P, et al.: CD8+ T-cell responses identify beta-cell autoimmunity in human type 1 diabetes. Diabetes 2007, 56:613–621.PubMedCrossRefGoogle Scholar
  40. 40.
    Seyfert-Margolis V, Gisler TD, Asare AL, et al.: Analysis of T-cell assays to measure autoimmune responses in subjects with type 1 diabetes: results of a blinded controlled study. Diabetes 2006, 55:2588–2594.PubMedCrossRefGoogle Scholar
  41. 41.
    Pugliese A, Zeller M, Fernandez A, Jr, et al.: The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTRIDDM2 susceptibility locus for type 1 diabetes. Nat Genet 1997, 15:293–297.PubMedCrossRefGoogle Scholar
  42. 42.
    Diabetes Prevention Trial-Type 1 Diabetes Study G: Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 2002, 346:1685–1691.CrossRefGoogle Scholar
  43. 43.
    Hassainya Y, Garcia-Pons F, Kratzer R, et al.: Identification of naturally processed HLA-A2-restricted proinsulin epitopes by reverse immunology. Diabetes 2005, 54:2053–2059.PubMedCrossRefGoogle Scholar
  44. 44.
    Blancou P, Mallone R, Martinuzzi E, et al.: Immunization of HLA class I transgenic mice identifies autoantigenic epitopes eliciting dominant responses in type 1 diabetes patients. J Immunol 2007, 178:7458–7466.PubMedGoogle Scholar
  45. 45.
    Ouyang Q, Standifer NE, Qin H, et al.: Recognition of HLA class I-restricted beta-cell epitopes in type 1 diabetes. Diabetes 2006, 55:3068–3074.PubMedCrossRefGoogle Scholar
  46. 46.
    Pinkse GG, Tysma OH, Bergen CA, et al.: Autoreactive CD8 T cells associated with beta cell destruction in type 1 diabetes. Proc Natl Acad Sci U S A 2005, 102:18425–18430.PubMedCrossRefGoogle Scholar
  47. 47.
    Standifer NE, Ouyang Q, Panagiotopoulos C, et al.: Identification of Novel HLA-A*0201-restricted epitopes in recent-onset type 1 diabetic subjects and antibody-positive relatives. Diabetes 2006, 55:3061–3067.PubMedCrossRefGoogle Scholar
  48. 48.
    Toma A, Haddouk S, Briand JP, et al.: Recognition of a subregion of human proinsulin by class I-restricted T cells in type 1 diabetic patients. Proc Natl Acad Sci U S A 2005, 102:10581–10586.PubMedCrossRefGoogle Scholar
  49. 49.
    Monti P, Scirpoli M, Rigamonti A, et al.: Evidence for in vivo primed and expanded autoreactive T cells as a specific feature of patients with type 1 diabetes. J Immunol 2007, 179:5785–5792.PubMedGoogle Scholar

Copyright information

© Current Medicine Group LLC 2008

Authors and Affiliations

  1. 1.INSERM U580Paris Cedex 15France

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