Control of Autoimmunity by Regulatory T Cells

  • Ethan M. Shevach
  • Rebecca S. McHugh
  • Angela M. Thornton
  • Ciriaco Piccirillo
  • Kannan Natarajan
  • David H. Margulies
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 490)


The development of autoimmune disease involves a breakdown in the mechanisms that control self vs non-self discrimimation. The primary mechanism that leads to self tolerance is thymic deletion of autoreactive T cells, but thymic deletion is not perfect and autoreactive T cells do escape to the periphery. Cells that escape thymic deletion are then subject to mechanisms of peripheral tolerance including the induction of anergy t as well as T cell ignorance/indifference of the recognition of autoantigens. However, anergy can be reversed and ignorant T cell populations have the potential to be activated when their target self-antigens are released into the lymphoid system during the course of an infectious insult or when activated by cross-reactive antigens present on infectious agents. Passive mechanisms for the induction of self tolerance may therefore be insufficient to control the activation of autoreactive T cells. Evidence has recently been obtained for an active mechanism of immune suppression in which a distinct subset of T cells suppresses the activation of autoreactive T cells that have escaped the other mechanisms of tolerance induction. Two experimental models have been developed which have allowed the definition of unique populations of regulatory T cells. In one model, autoimmunity is induced by depletion of regulatory T cells from adult animals, while in the second model, the development of regulatory T cells is abolished in neonatal animals.


Suppressor Cell Experimental Allergic Encephalomyelitis Autoimmune Gastritis Suppressor Cytokine Gastric Lymph Node 
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.
    Schwartz RH: A cell culture model for T lymphocyte anergy. Science 248:1349–1356, 1990PubMedCrossRefGoogle Scholar
  2. 2.
    Miller JFAP, Heath WR: Self-ignorance in the peripheral T-cell pool. Immunol Rev 133:131–150 1993PubMedCrossRefGoogle Scholar
  3. 3.
    Moller G: Dominant immunological tolerance. Immunol Rev 149:1–243 1996Google Scholar
  4. 4.
    Penhale WJ, Farmer A, Irvine WJ:. Thyroiditis in T cell-depleted rats: influence of strain, radiation dose, adjuvants and antilymphocyte serum. Clin Exp Immunol 21:362–375 1975PubMedGoogle Scholar
  5. 5.
    Penhale WJ, Stumbles PA, Huxtable CR, Sutherland RJ, Pethick DW: Induction of diabetes in PVG/c strain rats by manipulation of the immune system. Autoimmunity 7:169–179 1990PubMedCrossRefGoogle Scholar
  6. 6.
    Fowell D, Mason D: Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J Exp Med 177:627–636 1993PubMedCrossRefGoogle Scholar
  7. 7.
    Saoudi A, Seddon B, Heath V, Fowell D, Mason D: The physiological role of regulatory T cells in the prevention of autoimmunity: the function of the thymus in the generation of the regulatory T cell subset. Immunol Rev 149:195–216 1996PubMedCrossRefGoogle Scholar
  8. 8.
    Powrie F, Leach MW, Mauze S, Caddie LB, Coffman RL: Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C.B.-17 seid mice. Int Immunol 51:1461–1471 1993CrossRefGoogle Scholar
  9. 9.
    Powrie F, Correa-Oliveira R, Mauze S, Coffman RL: Regulatory interactions between CD45RBhigh and CD45RBiow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity. J Exp Med 179:589 1994PubMedCrossRefGoogle Scholar
  10. 10.
    Nishzuka Y, Sakakura T: Thymus and reproduction; sex linked dysgenesis of the gonad after neonatal thymectomy in mice. Science 166:753–755 1969CrossRefGoogle Scholar
  11. 11.
    Fukuma K, Sakaguchi S, Kuribayashi K, Chen W-L, Morishita R, Sekita K, Uchino H, Matsuda T: Immunologic and clinical studies on murine experimental autoimmune gastritis induced by neonatal thymectomy. Gastroenterology 94:274–283 1988PubMedGoogle Scholar
  12. 12.
    Sakaguchi S, Toda M, Asano M, Itoh M, Morse SS, Sakaguchi N: T cell-mediated maintenance of natural self-tolerance: its breakdown as a possible cause of various autoimmune diseases. J Autoimmun 9:211–220 1996PubMedCrossRefGoogle Scholar
  13. 13.
    Sakaguchi S, Ermak TH, Toda M, Berg LJ, Ho W, Fazekas de St. Groth B, Peterson PA, Sakaguchi N, Davis MM: Induction of autoimmune disease in mice by germline alteration of the T cell receptor gene expression. J Immunol 152:1471–1484 1994PubMedGoogle Scholar
  14. 14.
    Gleeson PA, Toh B-H, Van Driel I: Organ-specific autoimmunity induced by lymphopenia. Immunol Rev 149:97–126 1996PubMedCrossRefGoogle Scholar
  15. 15.
    Suri-Payer E, Kelm PJ, Cheever AW, Shevach EM: Pathogenesis of post-thymectomy autoimmune gastritis. Identification of anti-H/K adenosine triphosphatase-reactive T cells. J Immunol 157:1799–1805 1996PubMedGoogle Scholar
  16. 16.
    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 160:1212–1218 1998PubMedGoogle Scholar
  17. 17.
    Suri-Payer E, Amar AZ, McHugh R, Nataragan K, Margulies DH, Shevach EM: Postthymectomy autoimmune gastritis: fine specificity and pathogenicity of anti-H/K ATPase T cells. Eur J Immunol 29:669–677 1999PubMedCrossRefGoogle Scholar
  18. 18.
    Lafaille JJ, Nagashima K, Katsuki M, Tonegawa S: High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell 78:399–408 1994PubMedCrossRefGoogle Scholar
  19. 19.
    Katz JD, Wang B, Haskins K, Benoist C, Mathis D: Following a diabetogenic T cell from genesis through pathogenesis. Cell 74:1089–1097 1993PubMedCrossRefGoogle Scholar
  20. 20.
    Osman GE, Cheunsuk A, Allen AE, Chi E, Liggitt HD, Hood LE, Ladiges WC: Expression of a type II collagen-specific TCR transgene accelerates the onset of arthritis in mice. Int Immunol 10:1613–1633 1998PubMedCrossRefGoogle Scholar
  21. 21.
    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
  22. 22.
    Olivares-Villagomez D, Wang Y, Lafaille JJ: Regulatory CD4+ T cells expressing endogenous T cell receptor chains protect myelin basic protein-specific transgenic mice from spontaneous autoimmune encephalomyelitis. J Exp Med 188:1883–1894 1998PubMedCrossRefGoogle Scholar
  23. 23.
    Sakaguchi S, Fukuma K, Kuribayashi K, Matsuda T: Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med 161:72–87 1985PubMedCrossRefGoogle Scholar
  24. 24.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M: Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164 1995PubMedGoogle Scholar
  25. 25.
    Asano M, Toda M, Sakaguchi N, Sakaguchi S: Autoimmune disease as a consequence of a developmental abnormality of a T cell subpopulation. J Exp Med 184:387–396 1996PubMedCrossRefGoogle Scholar
  26. 26.
    Hammond KJL, Poulton LD, Palmisano LJ, Silveira PA, Godfrey DI, Baxter AG, a1ß-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
  27. 27.
    Thornton AM, Shevach EM: CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188:287–296 1998PubMedCrossRefGoogle Scholar
  28. 28.
    Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, Shimizu J, Sakaguchi S: Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells; induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 10:1969–1980 1998PubMedCrossRefGoogle Scholar
  29. 29.
    Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Otsuka F, Sakaguchi S: Thymus and autoimmunity; production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 162:5317 1999PubMedGoogle Scholar
  30. 30.
    Thorton AM, Shevach EM: Suppressor effector functionof CD4+CD25+ immunoregulatory T cells is antigen non-specific. J Immunol 164:183–190 2000Google Scholar
  31. 31.
    Papiernik M, Leite de Moraes M, Pontoux C, Vasseur F, Penit C: Regulatory CD4 T cells: expression of IL-2Ra chain, resistance to clonal deletion and IL-2 dependency. Int Immunol 10:371–378 1998PubMedCrossRefGoogle Scholar
  32. 32.
    Shevach EM: Regulatory T cells in autoimmunity. Ann Rev Immunol 18:423–449 2000CrossRefGoogle Scholar
  33. 33.
    Seddon B, Mason D: Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J Exp Med 189:877–881 1999PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Ethan M. Shevach
    • 1
  • Rebecca S. McHugh
    • 1
  • Angela M. Thornton
    • 1
  • Ciriaco Piccirillo
    • 1
  • Kannan Natarajan
    • 1
  • David H. Margulies
    • 1
  1. 1.Laboratory of ImmunologyNational Institute of Allergy and Infectious Diseases National Institutes of HealthBethesdaUSA

Personalised recommendations