Skip to main content

Advertisement

SpringerLink
Log in

Mechanisms of diabetic autoimmunity: II—Is diabetes a central or peripheral disorder of effector and regulatory cells?

  • Review
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Two competing hypotheses aiming to explain the onset of autoimmune reactions are discussed in the context of genetic and environmental predisposition to type 1 diabetes (T1D). The first hypothesis has evolved along characterization of the mechanisms of self-discrimination and attributes diabetic autoimmunity to escape of reactive T cells from central regulation in the thymus. The second considers frequent occurrence of autoimmune reactions within the immune homunculus, which are adequately suppressed by regulatory T cells originating from the thymus, and occasionally, insufficient suppression results in autoimmunity. Besides thymic dysfunction, deregulation of both effector and suppressor cells can in fact result from homeostatic aberrations at the peripheral level during initial stages of evolution of adaptive immunity. Pathogenic cells sensitized in the islets are efficiently expanded in the target tissue and pancreatic lymph nodes of lymphopenic neonates. In parallel, the same mechanisms of peripheral sensitization contribute to tolerization through education of naïve/effector T cells and expansion of regulatory T cells. Experimental evidence presented for each individual mechanism implies that T1D may result from a primary effector or suppressor immune abnormality. Disturbed self-tolerance leading to T1D may well result from peripheral deregulation of innate and adaptive immunity, with variable contribution of central thymic dysfunction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Boitard C, Larger E, Timsit J, Sempe P, Bach JF. IDDM: An islet or an immune disease? Diabetologia. 1994;37(Suppl 2):S90–8.

    Article  PubMed  Google Scholar 

  2. Homo-Delarche F, Boitard C. Autoimmune diabetes: the role of the islets of Langerhans. Immunol Today. 1996;17(10):456–60.

    Article  PubMed  CAS  Google Scholar 

  3. Jerne NK. The natural-selection theory of antibody formation. Proc Natl Acad Sci USA. 1955;41(11):849–56.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  4. Bretscher P, Cohn M. A theory of self-nonself discrimination. Science. 1970;169(3950):1042–9.

    Article  PubMed  CAS  Google Scholar 

  5. Burnet FM. A modification of Jerne’s theory of antibody production using the concept of clonal selection. CA Cancer J Clin. 1976;26(2):119–21.

    Article  PubMed  CAS  Google Scholar 

  6. Mackay IR. Autoimmunity since the 1957 clonal selection theory: a little acorn to a large oak. Immunol Cell Biol. 2008;86(1):67–71.

    Article  PubMed  CAS  Google Scholar 

  7. Rewers M, Bugawan TL, Norris JM, Blair A, Beaty B, Hoffman M, et al. Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY). Diabetologia. 1996;39(7):807–12.

    Article  PubMed  CAS  Google Scholar 

  8. Kupila A, Muona P, Simell T, Arvilommi P, Savolainen H, Hamalainen AM. Feasibility of genetic and immunological prediction of type I diabetes in a population-based birth cohort. Diabetologia. 2001;44(3):290–7.

    Article  PubMed  CAS  Google Scholar 

  9. Achenbach P, Bonifacio E, Koczwara K, Ziegler AG. Natural history of type 1 diabetes. Diabetes. 2005;54(Suppl 2):S25–31.

    Article  PubMed  CAS  Google Scholar 

  10. In’t Veld P, Lievens D, De Grijse J, Ling Z, Van der Auwera B, Pipeleers-Marichal M, et al. Screening for insulitis in adult autoantibody-positive organ donors. Diabetes. 2007;56(9):2400–4.

    Article  PubMed  CAS  Google Scholar 

  11. Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR. Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J Clin Invest. 2007;117(3):712–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  12. Elfving M, Lindberg B, Lynch K, Månsson M, Sundkvist G, Lernmark A, Ivarsson SA. Number of islet autoantibodies present in newly diagnosed type 1 diabetes children born to non-diabetic mothers is affected by islet autoantibodies present at birth. Pediatr Diabetes. 2008;9(2):127–34.

    Article  PubMed  Google Scholar 

  13. Serreze DV, Fleming SA, Chapman HD, Richard SD, Leiter EH, Tisch RM. B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. J Immunol. 1998;161(8):3912–8.

    PubMed  CAS  Google Scholar 

  14. Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TW, Atkinson MA, et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med. 2012;209(1):51–60.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. Danke NA, Koelle DM, Yee C, Beheray S, Kwok WW. Autoreactive T cells in healthy individuals. J Immunol. 2004;172(10):5967–72.

    Article  PubMed  CAS  Google Scholar 

  16. Askenasy EM, Askenasy N. Is autoimmune diabetes caused by aberrant immune activity or defective suppression of physiological self-reactivity? Autoimmun Rev. 2013;12(5):633–7.

    Article  PubMed  CAS  Google Scholar 

  17. Cohen IR, Young DB. Autoimmunity, microbial immunity and the immunological homunculus. Immunol Today. 1991;12(4):105–10.

    Article  PubMed  CAS  Google Scholar 

  18. Poletaev AB, Stepanyuk VL, Gershwin ME. Integrating immunity: the immunculus and self-reactivity. J Autoimmun. 2008;30(1–2):68–73.

    Article  PubMed  CAS  Google Scholar 

  19. Madi A, Bransburg-Zabary S, Kenett DY, Ben-Jacob E, Cohen IR. The natural autoantibody repertoire in newborns and adults: a current overview. Adv Exp Med Biol. 2012;750:198–212.

    Article  PubMed  CAS  Google Scholar 

  20. Hauben E, Roncarolo MG, Nevo U, Schwartz M. Beneficial autoimmunity in type 1 diabetes mellitus. Trends Immunol. 2005;26(5):248–53.

    Article  PubMed  CAS  Google Scholar 

  21. Koczwara K, Bonifacio E, Ziegler AG. Transmission of maternal islet antibodies and risk of autoimmune diabetes in offspring of mothers with type 1 diabetes. Diabetes. 2004;53(1):1–4.

    Article  PubMed  CAS  Google Scholar 

  22. Stanley HM, Norris JM, Barriga K, Hoffman M, Yu L, Miao D, et al. Diabetes Autoimmunity Study in the Young (DAISY). Is presence of islet autoantibodies at birth associated with development of persistent islet autoimmunity? Diabetes Care. 2004;27(2):497–502.

    Article  PubMed  CAS  Google Scholar 

  23. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151–64.

    PubMed  CAS  Google Scholar 

  24. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330–6.

    Article  PubMed  CAS  Google Scholar 

  25. Geenen V. Thymus and type 1 diabetes: an update. Diabetes Res Clin Pract. 2012;98(1):26–32.

    Article  PubMed  CAS  Google Scholar 

  26. Metzger TC, Anderson MS. Control of central and peripheral tolerance by Aire. Immunol Rev. 2011;241(1):89–103.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  27. Pugliese A, Zeller M, Fernandez A, Zalcberg LJ, Bartlett RJ, Ricordi C, et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet. 1997;15(3):293–7.

    Article  PubMed  CAS  Google Scholar 

  28. Delovitch TL, Singh B. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity. 1997;7(6):727–38.

    Article  PubMed  CAS  Google Scholar 

  29. Kishimoto H, Sprent J. A defect in central tolerance in NOD mice. Nat Immunol. 2001;2(11):1025–31.

    Article  PubMed  CAS  Google Scholar 

  30. Zucchelli S, Holler P, Yamagata T, Roy M, Benoist C, Mathis D. Defective central tolerance induction in NOD mice: Genomics and genetics. Immunity. 2005;22(3):385–96.

    Article  PubMed  CAS  Google Scholar 

  31. Lesage S, Hartley SB, Akkaraju S, Wilson J, Townsend M, Goodnow CC. Failure to censor forbidden clones of CD4 T cells in autoimmune diabetes. J Exp Med. 2002;196(9):1175–88.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  32. Bulek AM, Cole DK, Skowera A, Dolton G, Gras S, Madura F, et al. Structural basis for the killing of human beta cells by CD8(+) T cells in type 1 diabetes. Nat Immunol. 2012;13(3):283–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Enouz S, Carrié L, Merkler D. Bevan, Zehn D. Autoreactive T cells bypass negative selection and respond to self-antigen stimulation during infection. J Exp Med. 2012;209(10):1769–79.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  34. Dardenne M, Lepault F, Bendelac A, Bach JF. Acceleration of the onset of diabetes in NOD mice by thymectomy at weaning. Eur J Immunol. 1989;19(5):889–95.

    Article  PubMed  CAS  Google Scholar 

  35. Zou L, Mendez F, Martin-Orozco N, Peterson EJ. Defective positive selection results in T cell lymphopenia and increased autoimmune diabetes in ADAP-deficient BDC2.5-C57BL/6 mice. Eur J Immunol. 2008;38(4):986–94.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  36. Gagnerault MC, Lanvin O, Pasquier V, Garcia C, Damotte D, Lucas B, Lepault F. Autoimmunity during thymectomy-induced lymphopenia: role of thymus ablation and initial effector T cell activation timing in nonobese diabetic mice. J Immunol. 2009;183(8):4913–20.

    Article  PubMed  CAS  Google Scholar 

  37. Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med. 1996;184(2):387–96.

    Article  PubMed  CAS  Google Scholar 

  38. Dujardin HC, Burlen-Defranoux O, Boucontet L, Vieira P, Cumano A, Bandeira A. Regulatory potential and control of Foxp3 expression in newborn CD4+ T cells. Proc Natl Acad Sci USA. 2004;101(40):14473–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  39. Saoudi A, Seddon B, Fowell D, Mason D. The thymus contains a high frequency of cells that prevent autoimmune diabetes on transfer into prediabetic recipients. J Exp Med. 1996;184(6):2393–8.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  40. Suri-Payer E, Amar AZ, Thornton AM, Shevach EM. CD4+ CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J Immunol. 1998;160(3):1212–8.

    PubMed  CAS  Google Scholar 

  41. Murakami K, Maruyama H, Nishio A, Kuribayashi K, Inaba M, Inaba K, et al. Effects of intrathymic injection of organ-specific autoantigens, parietal cells, at the neonatal stage on autoreactive effector and suppressor T cell precursors. Eur J Immunol. 1993;23(4):809–14.

    Article  PubMed  CAS  Google Scholar 

  42. Ramanathan S, Bihoreau MT, Paterson AD, Marandi L, Gauguier D, Poussier P. Thymectomy and radiation-induced type 1 diabetes in nonlymphopenic BB rats. Diabetes. 2002;51(10):2975–81.

    Article  PubMed  CAS  Google Scholar 

  43. Berzins SP, Boyd RL, Miller JFAP. The role of the thymus and recent thymic migrants in the maintenance of the adult peripheral lymphocyte pool. J Exp Med. 1998;187(11):1839–48.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. Berzins SP, Godfrey DI, Miller JF, Boyd RL. A central role for thymic emigrants in peripheral T cell homeostasis. Proc Natl Acad Sci USA. 1999;96(17):9787–91.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  45. Bourgeois C, Hao Z, Rajewsky K, Potocnik AJ, Stockinger B. Ablation of thymic export causes accelerated decay of naive CD4 T cells in the periphery because of activation by environmental antigen. Proc Natl Acad Sci USA. 2008;105(25):8691–6.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Hoglund P, Mintern J, Waltzinger C, Heath C, Benoist C, Mathis D. Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J Exp Med. 1999;189(2):331–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  47. Trudeau JD, Dutz JP, Arany E, Hill DJ, Fieldus WE, Finegood DT. Neonatal β-cell apoptosis: a trigger for autoimmune diabetes? Diabetes. 2000;49(1):1–7.

    Article  PubMed  CAS  Google Scholar 

  48. Turley S, Poirot L, Hattori M, Benoist C, Mathis D. Physiological beta cell death triggers priming of self-reactive T-cells by dendritic cells in a type-1 diabetes model. J Exp Med. 2003;198(10):1527–37.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  49. O’Brien BA, Harmon BV, Cameron DP, Allan DJ. Apoptosis is the mode of beta-cell death responsible for the development of IDDM in the nonobese diabetic (NOD) mouse. Diabetes. 1997;46(5):750–7.

    Article  PubMed  Google Scholar 

  50. Scaglia L, Cahill CJ, Finegood DT, Bonner-Weir S. Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology. 1997;138(4):1736–41.

    PubMed  CAS  Google Scholar 

  51. Hill DJ, Strutt B, Arany E, Zaina S, Coukell S, Graham CF. Increased and persistent circulating insulin-like growth factor II in neonatal transgenic mice suppresses developmental apoptosis in the pancreatic islets. Endocrinology. 2000;141(3):1151–7.

    PubMed  CAS  Google Scholar 

  52. Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B. Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes. 2000;49(8):1325–33.

    Article  PubMed  CAS  Google Scholar 

  53. Katz JD, Wang B, Haskins K, Benoist C, Mathis D. Following a diabetogenic T cell from genesis through pathogenesis. Cell. 1993;74(6):1089–100.

    Article  PubMed  CAS  Google Scholar 

  54. Larger E, Bécourt C, Bach JF, Boitard C. Pancreatic islet beta cells drive T cell-immune responses in the nonobese diabetic mouse model. J Exp Med. 1995;181(5):1635–42.

    Article  PubMed  CAS  Google Scholar 

  55. Zekzer D, Wong FS, Ayalon O, Millet I, Altieri M, Shintani S, et al. GAD-reactive CD4+ Th1 cells induce diabetes in NOD/SCID mice. J Clin Invest. 1998;101(1):68–73.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  56. Wang B, Gonzalez A, Benoist C, Mathis D. The role of CD8+ T cells in initiation of insulin-dependent diabetes mellitus. Eur J Immunol. 1996;26(8):1762–9.

    Article  PubMed  CAS  Google Scholar 

  57. Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GSP, Robinson P, et al. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature. 1993;366(6450):69–72.

    Article  PubMed  CAS  Google Scholar 

  58. Tisch R, Yang XD, Singer SM, Liblau RS, Fugger L, Mcdevitt HO. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature. 1993;366(6450):72–5.

    Article  PubMed  CAS  Google Scholar 

  59. Wegmann DR, Norbury-Glaser M, Daniel D. Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur J Immunol. 1994;24(8):1853–7.

    Article  PubMed  CAS  Google Scholar 

  60. Halbout P, Briand JP, Bécourt C, Muller S, Boitard C. T cell response to preproinsulin I and II in the nonobese diabetic mouse. J Immunol. 2002;169(5):2436–43.

    Article  PubMed  CAS  Google Scholar 

  61. Candeias S, Katz J, Benoist C, Mathis D, Haskins K. Islet-specific T-cell clones from nonobese diabetic mice express heterogeneous T-cell receptors. Proc Natl Acad Sci USA. 1991;88(14):6167–70.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  62. Wooldridge L, Ekeruche-Makinde J, van den Berg HA, Skowera A, Miles JJ, Tan MP, et al. A single autoimmune T cell receptor recognizes more than a million different peptides. J Biol Chem. 2012;287(2):1168–77.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  63. Durinovic-Belló I. Autoimmune diabetes: the role of T cells, MHC molecules and autoantigens. Autoimmunity. 1998;27(3):159–77.

    Article  PubMed  Google Scholar 

  64. Tian J, Gregori S, Adorini A, Kaufman DL. The frequency of high avidity T-cells determines the hierarchy of determinant spreading. J Immunol. 2001;166(12):7144–57.

    Article  PubMed  CAS  Google Scholar 

  65. Tian J, Olcott AP, Kaufman DL. Antigen-based immunotherapy drives the precocious development of autoimmunity. J Immunol. 2002;169(11):6564–9.

    Article  PubMed  CAS  Google Scholar 

  66. von Herrath M, Holz A. Pathological changes in the islet milieu precede infiltration of islets and destruction of beta-cells by autoreactive lymphocytes in a transgenic model of virus-induced IDDM. J Autoimmun. 1997;10(3):231–8.

    Article  Google Scholar 

  67. Aspord C, Rome S, Thivolet C. Early events in islets and pancreatic lymph nodes in autoimmune diabetes. J Autoimmun. 2004;23(1):27–35.

    Article  PubMed  CAS  Google Scholar 

  68. Mintern JD, Sutherland RM, Lew AM, Shortman K, Carbone FR, Heath WR. Constitutive, but not inflammatory, cross-presentation is disabled in the pancreas of young mice. Eur J Immunol. 2002;32(4):1044–51.

    Article  PubMed  CAS  Google Scholar 

  69. Picarella DE, Kratz A, Li CB, Ruddle NH, Flavell RA. Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice. J Immunol. 1993;150(9):4136–50.

    PubMed  CAS  Google Scholar 

  70. Xie JH, Nomura N, Lu M, Chen SL, Koch GE, Weng Y, et al. Antibody-mediated blockade of the CXCR3 chemokine receptor results in diminished recruitment of T helper 1 cells into sites of inflammation. J Leukoc Biol. 2003;73(6):771–80.

    Article  PubMed  CAS  Google Scholar 

  71. Carvalho-Pinto C, García MI, Gómez L, Ballesteros A, Zaballos A, Flores JM. Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in non-obese diabetic mice. Eur J Immunol. 2004;34(2):548–57.

    Article  PubMed  CAS  Google Scholar 

  72. Campbell IL, Wong GH, Schrader JW, Harrison LC. Interferon-gamma enhances the expression of the major histocompatibility class I antigens on mouse pancreatic beta cells. Diabetes. 1985;34(11):1205–9.

    Article  PubMed  CAS  Google Scholar 

  73. Pujol-Borrell R, Todd I, Doshi M, Bottazzo GF, Sutton R, Gray D, et al. HLA class II induction in human islet cells by interferon-gamma plus tumour necrosis factor or lymphotoxin. Nature. 1987;325(6110):304–6.

    Article  Google Scholar 

  74. Kwon G, Corbett JA, Rodi CP, Sullivan P, McDaniel ML. Interleukin-1 beta-induced nitric oxide synthase expression by rat pancreatic beta-cells: evidence for the involvement of nuclear factor kappa B in the signaling mechanism. Endocrinology. 1995;136(11):4790–5.

    PubMed  CAS  Google Scholar 

  75. Falcone M, Sarvetnick N. The effect of local production of cytokines in the pathogenesis of insulin-dependent diabetes mellitus. Clin Immunol. 1999;90(1):2–9.

    Article  PubMed  CAS  Google Scholar 

  76. Kay TW, Darwiche R, Irawaty W, Chong MM, Pennington HL, Thomas HE. The role of cytokines as effectors of tissue destruction in autoimmunity. Adv Exp Med Biol. 2003;520:73–86.

    Article  PubMed  CAS  Google Scholar 

  77. Rabinovitch A, Suarez-Pinzon WL. Role of cytokines in the pathogenesis of autoimmune diabetes mellitus. Rev Endocr Metab Disord. 2003;4(3):291–9.

    Article  PubMed  CAS  Google Scholar 

  78. Gu D, Sarvetnick N. Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. Development. 1993;118(1):33–46.

    PubMed  CAS  Google Scholar 

  79. Petrik J, Arany E, McDonald TJ, Hill DJ. Apoptosis in the pancreatic islet cells of the neonatal rat is associated with a reduced expression of insulin-like growth factor II that may act as a survival factor. Endocrinology. 1998;139(6):2994–3004.

    PubMed  CAS  Google Scholar 

  80. Hill DJ, Petrik J, Arany E, McDonald TJ, Delovitch TL. Insulin-like growth factors prevent cytokine-mediated cell death in isolated islets of Langerhans from pre-diabetic non-obese diabetic mice. J Endocrinol. 1999;161(1):153–65.

    Article  PubMed  CAS  Google Scholar 

  81. Kaminitz A, Stein J, Yaniv I, Askenasy N. The vicious cycle of apoptotic beta-cell death in type 1 diabetes. Immunol Cell Biol. 2007;85(8):582–9.

    Article  PubMed  CAS  Google Scholar 

  82. Thomas HE, McKenzie MD, Angstetra E, Campbell PD, Kay TW. Beta cell apoptosis in diabetes. Apoptosis. 2009;14(12):1389–404.

    Article  PubMed  Google Scholar 

  83. Chen Z, Herman AE, Matos M, Mathis D, Benoist C. Where CD4+ CD25+ T reg cells impinge on autoimmune diabetes. J Exp Med. 2005;202(10):1387–97.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  84. Pearl-Yafe M, Iskovich S, Kaminitz A, Stein J, Yaniv I, Askenasy N. Does physiological beta cell turnover initiate autoimmune diabetes in the regional lymph nodes? Autoimmun Rev. 2006;5(5):338–43.

    Article  PubMed  Google Scholar 

  85. Gagnerault MC, Luan JJ, Lotton C, Lepault F. Pancreatic lymph nodes are required for priming of β cell reactive T cells in NOD mice. J Exp Med. 2002;196(3):369–77.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  86. Pang S, Zhang L, Wang H, Yi Z, Li L, Gao L, et al. CD8(+) T cells specific for beta cells encounter their cognate antigens in the islets of NOD mice. Eur J Immunol. 2009;39(10):2716–24.

    Article  PubMed  CAS  Google Scholar 

  87. Wang J, Tsai S, Shameli A, Yamanouchi J, Alkemade G, Santamaria P. In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8+ T cell inflammation. Proc Natl Acad Sci USA. 2010;107(20):9317–22.

    Article  PubMed Central  PubMed  Google Scholar 

  88. Lennon GP, Bettini M, Burton AR, Vincent E, Arnold PY, Santamaria P, Vignali DA. T cell islet accumulation in type 1 diabetes is a tightly regulated, cell-autonomous event. Immunity. 2009;31(4):643–53.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  89. Graham KL, Krishnamurthy B, Fynch S, Mollah ZU, Slattery R, Santamaria P, et al. Autoreactive cytotoxic T lymphocytes acquire higher expression of cytotoxic effector markers in the islets of NOD mice after priming in pancreatic lymph nodes. Am J Pathol. 2011;178(6):2716–25.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  90. Adkins B, Williamson T, Guevara P, Bu Y. Murine neonatal lymphocytes show rapid early cell cycle entry and cell division. J Immunol. 2003;170(9):4548–56.

    Article  PubMed  CAS  Google Scholar 

  91. Min B, McHugh R, Sempowski GD, Mackall C, Foucras G, Paul WE. Neonates support lymphopenia-induced proliferation. Immunity. 2003;18(1):131–40.

    Article  PubMed  CAS  Google Scholar 

  92. Kieper WC, Jameson SC. Homeostatic expansion and phenotypic conversion of naïve T cells in response to self peptide/MHC ligands. Proc Natl Acad Sci USA. 1999;96(23):13306–11.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  93. Ichii H, Sakamoto A, Hatano M, Okada S, Toyama H, Taki S, et al. Role for Bcl-6 in the generation and maintenance of memory CD8+ T cells. Nat Immunol. 2002;3(6):558–63.

    Article  PubMed  CAS  Google Scholar 

  94. Le Campion A, Bourgeois C, Lambolez F, Martin B, Leaument S, Dautigny N, et al. Naive T cells proliferate strongly in neonatal mice in response to self-peptide/self-MHC complexes. Proc Natl Acad Sci USA. 2002;99(7):4538–43.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  95. Horwitz MS, Ilic A, Fine C, Rodriguez E, Sarvetnick N. Presented antigen from damaged pancreatic beta cells activates autoreactive T cells in virus-mediated autoimmune diabetes. J Clin Invest. 2002;109(1):79–87.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  96. Zhang Y, O’Brien B, Trudeau J, Tan R, Santamaria P, Dutz JP. In situ beta cell death promotes priming of diabetogenic CD8 T lymphocytes. J Immunol. 2002;168(3):1466–72.

    Article  PubMed  CAS  Google Scholar 

  97. Hugues S, Mougneau E, Ferlin W, Jeske D, Hofman P, Homann D, et al. Tolerance to islet antigens and prevention from diabetes induced by limited apoptosis of pancreatic beta cells. Immunity. 2002;16(2):169–81.

    Article  PubMed  CAS  Google Scholar 

  98. Yarkoni S, Kaminitz A, Sagiv Y, Askenasy N. Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice. Diabetologia. 2010;53(2):356–68.

    Article  PubMed  CAS  Google Scholar 

  99. Sai P, Senecat O, Martignat L, Gouin E. Neonatal injections of cyclosporin enhance autoimmune diabetes in non-obese diabetic mice. Clin Exp Immunol. 1994;97(1):138–45.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  100. Xia CQ, Peng R, Qiu Y, Annamalai M, Gordon D, Clare-Salzler MJ. Transfusion of apoptotic beta-cells induces immune tolerance to beta-cell antigens and prevents type 1 diabetes in NOD mice. Diabetes. 2007;56(8):2116–23.

    Article  PubMed  CAS  Google Scholar 

  101. Kurts C, Kosaka H, Carbone FR, Miller J, Heath WR. Class I—restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8+ T cells. J Exp Med. 1997;186(2):239–45.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  102. Alferink J, Tafuri A, Vestweber D, Hallmann R, Hämmerling GJ, Arnold B. Control of neonatal tolerance to tissue antigens by peripheral T cell trafficking. Science. 1998;282(5392):1338–41.

    Article  PubMed  CAS  Google Scholar 

  103. Heath WR, Kurts C, Miller JF, Carbone FR. Cross-tolerance: a pathway for inducing tolerance to peripheral tissue antigens. J Exp Med. 1998;187(10):1549–53.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  104. Mukhopadhaya A, Hanafusa T, Jarchum I, Chen YG, Iwai Y, Serreze DV, et al. Selective delivery of beta cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice. Proc Natl Acad Sci USA. 2008;105(17):6374–9.

    Article  PubMed Central  PubMed  Google Scholar 

  105. Ganguly D, Haak S, Sisirak V, Reizis B. The role of dendritic cells in autoimmunity. Nat Rev Immunol. 2013;13(8):566–77.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  106. Price JD, Tarbell KV. The Role of dendritic cell subsets and innate immunity in the pathogenesis of type 1 diabetes and other autoimmune diseases. Front Immunol. 2015;6:288.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  107. Kanagawa O, Militech A, Vaupel BA. Regulation of diabetes development by regulatory T cells in pancreatic islet antigen-specific TCR transgenic nonobese diabetic mice. J Immunol. 2002;168(2):6159–64.

    Article  PubMed  CAS  Google Scholar 

  108. Chen C, Lee WH, Yun P, Snow P, Liu CP. Induction of autoantigen-specific Th2 and Tr1 regulatory T cells and modulation of autoimmune diabetes. J Immunol. 2003;171(2):733–44.

    Article  PubMed  CAS  Google Scholar 

  109. Zwar TD, Read S, van Driel IR, Gleeson PA. CD4+ CD25+ regulatory T cells inhibit the antigen-dependent expansion of self-reactive T cells in vivo. J Immunol. 2006;176(3):1609–17.

    Article  PubMed  CAS  Google Scholar 

  110. Tonkin DR, He J, Barbour G, Haskins K. Regulatory T cells prevent transfer of type 1 diabetes in NOD mice only when their antigen is present in vivo. J Immunol. 2008;181(7):4516–22.

    Article  PubMed  CAS  Google Scholar 

  111. Piccirillo CA, Tritt M, Sgouroudis E, Albanese A, Pyzik M, Hay V. Control of type 1 autoimmune diabetes by naturally occurring CD4+ CD25+ regulatory T lymphocytes in neonatal NOD mice. Ann N Y Acad Sci. 2005;1051:72–87.

    Article  PubMed  CAS  Google Scholar 

  112. Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol. 2006;7(1):83–92.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  113. Kaminitz A, Mizrahi K, Ash S, Ben-Nun A, Askenasy N. Stable activity of diabetogenic cells with age in NOD mice: dynamics of reconstitution and adoptive diabetes transfer in immunocompromised mice. Immunology. 2014;142(3):465–73.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  114. Barthlott T, Kassiotis G, Stockinger B. T cell regulation as a side effect of homeostasis and competition. J Exp Med. 2003;197(4):451–60.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  115. Askenasy EM, Askenasy N, Askenasy JJ. Does lymphopenia preclude restoration of immune homeostasis? The particular case of type 1 diabetes. Autoimmun Rev. 2010;9(10):687–90.

    Article  PubMed  CAS  Google Scholar 

  116. Ash S, Yarkoni S, Askenasy N. Lymphopenia is detrimental to therapeutic approaches to type 1 diabetes using regulatory T cells. Immunol Res. 2014;58(1):101–5.

    Article  PubMed  CAS  Google Scholar 

  117. Kaminitz A, Mizrahi K, Askenasy N. Surge in regulatory T cells does not prevent onset of hyperglycemia in NOD mice: immune profiles do not correlate with disease severity. Autoimmunity. 2014;47(2):105–12.

    Article  PubMed  CAS  Google Scholar 

  118. Le Campion A, Gagnerault MC, Auffray C, Bécourt C, Poitrasson-Rivière M, Lallemand E, et al. Lymphopenia-induced spontaneous T-cell proliferation as a cofactor for autoimmune disease development. Blood. 2009;114(9):1784–93.

    Article  PubMed  CAS  Google Scholar 

  119. Takacs K, Altmann DM. The case against epitope spread in experimental allergic encephalomyelitis. Immunol Rev. 1998;164:101–10.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Leah and Edward M. Frankel Laboratory of Experimental Bone Marrow Transplantation, 14 Kaplan Street, 49202, Petach Tikva, Israel

    Nadir Askenasy

Authors
  1. Nadir Askenasy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nadir Askenasy.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Askenasy, N. Mechanisms of diabetic autoimmunity: II—Is diabetes a central or peripheral disorder of effector and regulatory cells?. Immunol Res 64, 36–43 (2016). https://doi.org/10.1007/s12026-015-8725-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-015-8725-2

Keywords

Search

Navigation