Control of Autoreactive T Cell Activation by Immunoregulatory T Cells (Art)

  • Jean-François Bach
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 490)


It had been known for several decades that autoimmunity does not necessarily lead to pathological manifestations. In fact, such harmless autoimmunity can be considered as physiologic since it is observed in all healthy individuals, both at the B cell level (natural autoantibodies)1 and at the T cell level (one can derive MHC class II or organ specific T cell lines from normal peripheral blood lymphocytes)2 Progression to pathogenic autoimmunity requires autoreactive B and/or T cell activation. This requirement is well illustrated by the classic double transgenic mouse experiment in which coexistence of overexpression of a target antigen (a viral protein) in the ß cells of the islets of Langerhans and overexpression of T cells specific for this antigen does not lead to diabetes without activation of the said T cells by infection with the specific virus.3 The question is thus posed of the origin and the modalities of such activation of autoreactive B or T cells in spontaneously occurring autoimmune diseases. On the other hand, it appears that the progression to clinical manifestations in these diseases is often very slow and preceded by a long phase of preclinical autoimmunity which is apparently more intense than the physiologic autoimmunity mentioned above but yet insufficient to create clinically relevant lesions. This preclinical autoimmune phase is particularly well documented in insulin-dependent diabetes mellitus (IDDM), both in the non-obese diabetic (NOD) mouse and in human disease.4 The question is to determine what are the mechanisms responsible for such a control of disease progression. Are they related to those preventing undesirable clinical expression of physiological autoimmunity? In this chapter, data will be reviewed that indicate that such mechanisms essentially involve CD4 T cells which begin to be characterized in terms of their phenotype, their autoantigen specificity, their mode of action, their genetic control and their sensitivity to environmental factors.


Nonobese Diabetic Mouse Cyclophosphamide Treatment Costimulatory Pathway Autoimmune Polyendocrine Syndrome Natural Autoantibody 
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  1. 1.
    Avrameas S, Ternynck T: The natural autoantibodies system: between hypotheses and facts. Mol Immunol 30:1133–1142, 1993PubMedCrossRefGoogle Scholar
  2. 2.
    Shanmugam A, Copie-Bergman C, Hashim G, Rebibo D, Jais JP, Bach JF, Bach MA, Tournier-Lasserve E: Healthy monozygous twins do not recognize identical T cell epitopes on the myelin basic protein autoantigen. Eur J Immunol 24:2299–2303, 1994PubMedCrossRefGoogle Scholar
  3. 3.
    Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, Malissen B, Zinkernagel RM, Hengartner H: Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65:305–317,1991PubMedCrossRefGoogle Scholar
  4. 4.
    Bach JF: Insulin-dependent diabetes mellitus as an autoimmune disease. Endocrine Rev 15:516–542,1994Google Scholar
  5. 5.
    Miller SD, Vanderlugt CL, Begolka WS, Pao W, Yauch RL, Neville KL, Katz Levy Y, Carrizosa A, Kim BS: Persistent infection with Theiler’s virus leads to CNS autoimmunity via epitope spreading. Nat Med 3:1133–1136,1997PubMedCrossRefGoogle Scholar
  6. 6.
    Weigle WO, Nakamura RM: Perpetuation of autoimmune thyroiditis and production of secondary renal lesions following periodic injections of aqueous preparations of altered thyroglobulin. Clin Exp Immunol 4:645–657,1969PubMedGoogle Scholar
  7. 7.
    Weigle WO: The production of thyroiditis and antibody following injection of unaltered thyroglobulin without adjuvant into rabbits previously stimulated with altered thyroglobulin. J Exp Med 122:1049–1062,1965PubMedCrossRefGoogle Scholar
  8. 8.
    Dardenne M, Lepault F, Bendelac A, Bach JF: Acceleration of the onset of diabetes in NOD mice by thymectomy at weaning. Eur J Immunol 19:889–895,1989PubMedCrossRefGoogle Scholar
  9. 9.
    Yasunami R, Bach JF: Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice. Eur J Immunol 18:481–484,1988PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang ZL, Georgiou HM, Mandel TE: The effect of cyclophosphamide treatment on lymphocyte subsets in the nonobese diabetic mouse: a comparison of various lymphoid organs. Autoimmunity 15:1–10,1993PubMedCrossRefGoogle Scholar
  11. 11.
    Charlton B, Bacelj A, Slattery RM, Mandel TE: Cyclophosphamide-induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus. Diabetes 38:441–447,1989PubMedCrossRefGoogle Scholar
  12. 12.
    Lenschow DJ, Herold KC, Rhee L, Patel B, Koons A, Qin HY, Fuchs E, Singh B, Thompson CB, Bluestone JA: CD28/B7 regulation of Thl and Th2 subsets in the development of autoimmune diabetes. Immunity 5:285–293,1996PubMedCrossRefGoogle Scholar
  13. 13.
    Green JM, Noel PJ, Sperling AI, Walunas TL, Gray GS, Bluestone JA, Thompson CB: Absence of B7-dependent responses in CD28-deficient mice. Immunity 1:501–508,1994PubMedCrossRefGoogle Scholar
  14. 14.
    Luhder F, Hoglund P, Allison JP, Benoist C, Mathis D: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J Exp Med 187:427–432,1998PubMedCrossRefGoogle Scholar
  15. 15.
    Nishizuka Y, Sakakura T: Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166:753–755,1969PubMedCrossRefGoogle Scholar
  16. 16.
    Sakaguchi S, Takahashi T, Nishizuka Y: Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer. J Exp Med 156:1565–1576,1982PubMedCrossRefGoogle Scholar
  17. 17.
    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 184:2393–2398,1996PubMedCrossRefGoogle Scholar
  18. 18.
    Groux H, Powrie F: Regulatory T cells and inflammatory bowel disease. Immunol Today 20:442–445,1999PubMedCrossRefGoogle Scholar
  19. 19.
    Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F, Sakaguchi S: Thymus and autoimmunity: production of CD25+CD4+ naturally anergie and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 162:5317–5326,1999PubMedGoogle Scholar
  20. 20.
    Rossini AA, Faustman D, Woda BA, Like AA, Szymanski I, Mordes JP: Lymphocyte transfusions prevent diabetes in the Bio-Breeding/Worcester rat. J Clin Invest 74:3946,1984CrossRefGoogle Scholar
  21. 21.
    Seddon B, Saoudi A, Nicholson M, Mason D: CD4+CD8- thymocytes that express Lselectin protect rats from diabetes upon adoptive transfer. Eur J Immunol 26:27022708,1996Google Scholar
  22. 22.
    Herbelin A, Gombert JM, Lepault F, Bach JF, Chatenoud L: Mature mainstream TCR alpha beta(+)CD4(+) thymocytes expressing L-selectin mediate “active tolerance” in the nonobese diabetic mouse. J Immunol 161:2620–2628,1998PubMedGoogle Scholar
  23. 23.
    Lepault F, Gagnerault MC: Characterization of peripheral regulatory CD4(+) T cells that prevent diabetes onset in nonobese diabetic mice. J Immunol 164:240–247,1900Google Scholar
  24. 24.
    Lepault F, Gagnerault MC, Faveeuw C, Bazin H, Boitard C: Lack of L-selectin expression by cells transferring diabetes in NOD mice: insights into the mechanisms involved in diabetes prevention by Mel-14 antibody treatment. Eur J Immunol 25:15021507,1995Google Scholar
  25. 25.
    Shimada A, Rohane P, Fathman CG, Charlton B: Pathogenic and protective roles of CD45RB(low) CD4+ cells correlate with cytokine profiles in the spontaneously autoimmune diabetic mouse. Diabetes 45:71–78,1996PubMedCrossRefGoogle Scholar
  26. 26.
    Martins TC, Aguas AP: A role for CD45RB(Low) CD38(+) T cells and costimulatory pathways of T-cell activation in protection of non-obese diabetic (NOD) mice from diabetes. Immunology 96:600–605,1999PubMedCrossRefGoogle Scholar
  27. 27.
    King KJ, Hagan RP, Mieno M, McCullagh P: Cellular interactions during the development of autoimmunity in a fetal lamb model of self-antigen deprivation. Clin Immunol Immunopathol 88:56–64,1998PubMedCrossRefGoogle Scholar
  28. 28.
    McCullagh P: Curtailment of autoimmunity following parabiosis with a normal partner. Immunology 71:595–597,1990PubMedGoogle Scholar
  29. 29.
    McCullagh P: The significance of immune suppression in normal self tolerance. Immunol Rev 149:127–153,1996PubMedCrossRefGoogle Scholar
  30. 30.
    Seddon B, Mason D: Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J Exp Med 189:877–882,1999PubMedCrossRefGoogle Scholar
  31. 31.
    Taguchi O, Nishizuka Y: Experimental autoimmune orchitis after neonatal thymectomy in the mouse. Clin Exp Immunol 46:425–434,1981PubMedGoogle Scholar
  32. 32.
    Taguchi O, Nishizuka Y: Self tolerance and localized autoimmunity. Mouse models of autoimmune disease that suggest tissue-specific suppressor T cells are involved in self tolerance. J Exp Med 165:146–156,1987PubMedCrossRefGoogle Scholar
  33. 33.
    Smith H, Sakamoto Y, Kasai K, Tung KS: Effector and regulatory cells in autoimmune oophoritis elicited by neonatal thymectomy. J Immunol 147:2928–2933,1991PubMedGoogle Scholar
  34. 34.
    Taguchi O, Kontani K, Ikeda H, Kezuka T, Takeuchi M, Takahashi T, Takahashi T: Tissue-specific suppressor T cells involved in self-tolerance are activated extrathymically by self-antigens. Immunology 82:365–369,1994PubMedGoogle Scholar
  35. 35.
    Alderuccio F, Toh BH, Tan SS, Gleeson PA, Van Driel IR: An autoimmune disease with multiple molecular targets abrogated by the transgenic expression of a single autoantigen in the thymus. J Exp Med 178:419–426,1993PubMedCrossRefGoogle Scholar
  36. 36.
    Tisch R, Liblau RS, Yang XD, Liblau P, McDevitt HO: Induction of GAD65-specific regulatory T-cells inhibits ongoing autoimmune diabetes in nonobese diabetic mice. Diabetes 47:894–899,1998PubMedCrossRefGoogle Scholar
  37. 37.
    Elias D, Meilin A, Ablamunits V, Birk OS, Carmi P, Konen-Waisman S, Cohen IR: Hsp60 peptide therapy of NOD mouse diabetes induces a Th2 cytokine burst and downregulates autoimmunity to various beta-cell antigens. Diabetes 46:758–764,1997PubMedCrossRefGoogle Scholar
  38. 38.
    Tian JD, Clare-Salzler M, Herschenfeld A, Middleton B, Newman D, Mueller R, Arita S, Evans C, Atkinson MA, Mullen Y, Sarvetnick N, Tobin AJ, Lehmann PV, Kaufman DL: Modulating autoimmune responses to GAD inhibits disease progression and prolongs islet graft survival in diabetes-prone mice. Nat Med 2:1348–1353,1996PubMedCrossRefGoogle Scholar
  39. 39.
    Chai JG, Bartok I, Chandler P, Vendetti S, Antoniou A, Dyson J, Lechler R: Anergic T cells act as suppressor cells in vitro and in vivo. Eur J Immunol 29:686–692,1999PubMedCrossRefGoogle Scholar
  40. 40.
    Boitard C, Yasunami R, Dardenne M, Bach JF: T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice. J Exp Med 169:1669–1680,1989PubMedCrossRefGoogle Scholar
  41. 41.
    Bendelac A, Rivera MN, Park SH, Roark JH: Mouse CD1-specific NK1 T cells: development, specificity, and function. Annu Rev Immunol 15:535–562,1997PubMedCrossRefGoogle Scholar
  42. 42.
    Bendelac A, Hunziker RD, Lantz O: Increased interleukin 4 and immunoglobulin E production in transgenic mice overexpressing NK1 T cells. J Exp Med 184:12851293,1996Google Scholar
  43. 43.
    Gombert JM, Herbelin A, Tancrede-Bohin E, Dy M, Carnaud C, Bach JF: Early quantitative and functional deficiency of NK1(+)- like thymocytes in the NOD mouse. Eur J Immunol 26:2989–2998,1996PubMedCrossRefGoogle Scholar
  44. 44.
    Yoshimoto T, Bendelac A, Hu-Li J, Paul WE: Defective IgE production by SJL mice is linked to the absence of CD4+, NK1.1+ T cells that promptly produce interleukin 4. Proc Natl Acad Sci USA 92:11931–11934,1995PubMedCrossRefGoogle Scholar
  45. 45.
    Gombert JM, Tancrede-Bohin E, Hameg A, Leite-de-Moraes MC, Vicari A, Bach JF, Herbelin A: IL-7 reverses NK1+ T cell-defective IL-4 production in the non-obese diabetic mouse. Int Immunol 8:1751–1758,1996PubMedCrossRefGoogle Scholar
  46. 46.
    Lehuen A, Lantz O, Beaudoin L, Laloux V, Carnaud C, Bendelac A, Bach JF, Monteiro RC: Overexpression of natural killer T cells protects V alpha 14-J alpha 281 transgenic nonobese diabetic mice against diabetes. J Exp Med 188:1831–1839,1998PubMedCrossRefGoogle Scholar
  47. 47.
    Hammond KJ, Poulton LD, Palmisano Li, Silveira PA, Godfrey DI, Baxter AG: alpha/beta-T cell receptor (TCR)(+)CD4(-)CD8(-) (NKT) thymocytes prevent insulin-dependent diabetes mellitus in nonobese diabetic (NOD)/Lt mice by the influence of interleukin (IL)-4 and/or IL-10. J Exp Med 187:1047–1056,1998PubMedCrossRefGoogle Scholar
  48. 48.
    Wang B, Gonzalez A, Hoglund P, Katz JD, Benoist C, Mathis D: Interleukin-4 deficiency does not exacerbate disease in NOD mice. Diabetes 47:1207–1211,1998PubMedCrossRefGoogle Scholar
  49. 49.
    Bjorses P, Aaltonen J, Horelli-Kuitunen N, Yaspo ML, Peltonen L: Gene defect behind APECED: a new clue to autoimmunity. Hum Mol Genet 7:1547–1553,1998PubMedCrossRefGoogle Scholar
  50. 50.
    Ohsugi T, Kurosawa T: Increased incidence of diabetes mellitus in specific pathogen-eliminated offspring produced by embryo transfer in NOD mice with low incidence of the disease. Lab Anim Sci 44:386–388,1994PubMedGoogle Scholar
  51. 51.
    Hansen AK, Josefsen K, Pedersen C, Buschard K: Neonatal stimulation of beta-cells reduces the incidence and delays the onset of diabetes in a barrier-protected breeding colony of BB rats. Exp Clin Endocrinol 101:189–193,1993PubMedCrossRefGoogle Scholar
  52. 52.
    Like AA, Guberski DL, Butler L: Influence of environmental viral agents on frequency and tempo of diabetes mellitus in BB/Wor rats. Diabetes 40:259–262,1991PubMedCrossRefGoogle Scholar
  53. 53.
    Bach JF: Predictive medicine in autoimmune diseases: from the identification of genetic predisposition and environmental influence to precocious immunotherapy. Clin Immunol Immunopathol 72:156–161,1994PubMedCrossRefGoogle Scholar
  54. 54.
    Qin HY, Sadelain MW, Hitchon C, Lauzon J, Singh B: Complete Freund’s adjuvant-induced T cells prevent the development and adoptive transfer of diabetes in nonobese diabetic mice. J Immunol 150:2072–2080,1993PubMedGoogle Scholar
  55. 55.
    Chatenoud L, Thervet E, Primo J, Bach JF: Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA 91:123–127,1994PubMedCrossRefGoogle Scholar
  56. 56.
    Chatenoud L, Primo J, Bach JF: CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol 158:2947–2954,1997PubMedGoogle Scholar
  57. 57.
    Arreaza GA, Cameron MJ, Jaramillo A, Gill BM, Hardy D, Laupland KB, Rapoport MJ, Zucker P, Chakrabarti S, Chensue SW, Qin HY, Singh B, Delovitch TL: Neonatal activation of CD28 signaling overcomes T cell anergy and prevents autoimmune diabetes by an IL-4-dependent mechanism. J Clin Invest 100:2243–2253,1997PubMedCrossRefGoogle Scholar
  58. 58.
    Hayward AR, Schriber M, Cooke A, Waldmann H: Prevention of diabetes but not insulitis in NOD mice injected with antibody to CD4. J Autoimmun 6:301–310,1993PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Jean-François Bach
    • 1
  1. 1.Hôpital NeckerINSERM U 25ParisFrance

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