Advertisement

Springer Seminars in Immunopathology

, Volume 28, Issue 1, pp 3–16 | Cite as

Regulatory T cells in experimental autoimmune disease

  • Elisabeth Suri-PayerEmail author
  • Benedikt Fritzsching
Review

Abstract

During the past 10 years, CD4+CD25+Foxp3+ regulatory T cells (Treg) have been extensively studied for their function in autoimmune disease. This review summarizes the evidence for a role of Treg in suppression of innate and adaptive immune responses in experimental models of autoimmunity including arthritis, colitis, diabetes, autoimmune encephalomyelitis, lupus, gastritis, oophoritis, prostatitis, and thyroiditis. Antigen-specific activation of Treg, but antigen-independent suppressive function, emerges as a common paradigm derived from several disease models. Treg suppress conventional T cells (Tcon) by direct cell contact in vitro. However, downmodulation of dendritic cell function and secretion of inhibitory cytokines such as IL-10 and TGF-β might underlie Treg function in vivo. The final outcome of autoimmunity vs tolerance depends on the balance between stimulatory signals (Toll-like receptor engagement, costimulation, and antigen dose) and inhibitory signals from Treg. Whereas most experimental settings analyze the capacity of Treg to prevent onset of autoimmune disease, more recent efforts indicate successful treatment of ongoing disease. Thus, Treg are on the verge of moving from experimental animal models into clinical applications in humans.

Keywords

Foxp3 Regulatory mechanism Antigen specificity Targets Cure 

Notes

Acknowledgements

We would like to thank all the researchers that have contributed to our knowledge about Treg in autoimmunity, and apologize to all of those we could not cite due to space constraints. We would like to thank P. Krammer, T. Trollmo, A. Cerwenka, J. Haas, V. Umansky, P. Beckhove, K. Hochweller, N. Oberle, N. Eberhardt, and I. Galani for critically reading the manuscript and helpful discussions.

References

  1. 1.
    Shevach EM (2000) Regulatory T cells in autoimmmunity*. Annu Rev Immunol 18:423PubMedGoogle Scholar
  2. 2.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) 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 155:1151PubMedGoogle Scholar
  3. 3.
    Suri-Payer E, Amar AZ, Thornton AM, Shevach EM (1998) 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 160:1212PubMedGoogle Scholar
  4. 4.
    Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F, Sakaguchi S (1999) 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 162:5317PubMedGoogle Scholar
  5. 5.
    Asano M, Toda M, Sakaguchi N, Sakaguchi S (1996) Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 184:387PubMedGoogle Scholar
  6. 6.
    Suri-Payer E, Amar AZ, McHugh R, Natarajan K, Margulies DH, Shevach EM (1999) Post-thymectomy autoimmune gastritis: fine specificity and pathogenicity of anti-H/K ATPase-reactive T cells. Eur J Immunol 29:669PubMedGoogle Scholar
  7. 7.
    McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, Byrne MC (2002) CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16:311PubMedGoogle Scholar
  8. 8.
    Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3:135PubMedGoogle Scholar
  9. 9.
    Bruder DM, Probst-Kepper, Westendorf AM, Geffers R, Beissert S, Loser K, von Boehmer H, Buer J, Hansen W (2004) Neuropilin-1: a surface marker of regulatory T cells. Eur J Immunol 34:623PubMedGoogle Scholar
  10. 10.
    Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA (2004) Role of LAG-3 in regulatory T cells. Immunity 21:503PubMedGoogle Scholar
  11. 11.
    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 192:295PubMedGoogle Scholar
  12. 12.
    Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303PubMedGoogle Scholar
  13. 13.
    Thornton AM, Shevach EM (2000) Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 164:183PubMedGoogle Scholar
  14. 14.
    Huehn J, Siegmund K, Lehmann JC, Siewert C, Haubold U, Feuerer M, Debes GF, Lauber J, Frey O, Przybylski GK, Niesner U, de la Rosa M, Schmidt CA, Brauer R, Buer J, Scheffold A, Hamann A (2004) Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+regulatory T cells. J Exp Med 199:303PubMedGoogle Scholar
  15. 15.
    Suffia I, Reckling SK, Salay G, Belkaid Y (2005) A role for CD103 in the retention of CD4+CD25+ Treg and control of Leishmania major infection. J Immunol 174:5444PubMedGoogle Scholar
  16. 16.
    Fisson S, Darrasse-Jeze G, Litvinova E, Septier F, Klatzmann D, Liblau R, Salomon BL (2003) Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J Exp Med 198:737PubMedGoogle Scholar
  17. 17.
    Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057PubMedGoogle Scholar
  18. 18.
    Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4:337PubMedGoogle Scholar
  19. 19.
    Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330PubMedGoogle Scholar
  20. 20.
    Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329PubMedGoogle Scholar
  21. 21.
    Wan YY, Flavell RA (2005) Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci USA 102:5126PubMedGoogle Scholar
  22. 22.
    Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF (2004) Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172:5149PubMedGoogle Scholar
  23. 23.
    Fantini MC, Becker C, Tubbe I, Nikolaev A, Lehr HA, Galle PR, Neurath MF (2005) TGF-{beta} induced Foxp3+ regulatory T cells suppress Th1-mediated experimental colitis. Gut 55(5):671–680PubMedGoogle Scholar
  24. 24.
    Apostolou I, von Boehmer H (2004) In vivo instruction of suppressor commitment in naive T cells. J Exp Med 199:1401PubMedGoogle Scholar
  25. 25.
    Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6:1219PubMedGoogle Scholar
  26. 26.
    Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6:1142PubMedGoogle Scholar
  27. 27.
    Bayer AL, Yu A, Adeegbe D, Malek TR (2005) Essential role for interleukin-2 for CD4(+)CD25(+) T regulatory cell development during the neonatal period. J Exp Med 201:769PubMedGoogle Scholar
  28. 28.
    D’Cruz LM, Klein L (2005) Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 6:1152PubMedGoogle Scholar
  29. 29.
    Setoguchi R, Hori S, Takahashi T, Sakaguchi S (2005) Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 201:723PubMedGoogle Scholar
  30. 30.
    Huber S, Schramm C, Lehr HA, Mann A, Schmitt S, Becker C, Protschka M, Galle PR, Neurath MF, Blessing M (2004) Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol 173:6526PubMedGoogle Scholar
  31. 31.
    Marie JC, Letterio JJ, Gavin M, Rudensky AY (2005) TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 201:1061PubMedGoogle Scholar
  32. 32.
    Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK, Zheng XX, Strom TB, Bluestone JA (2003) Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 171:3348PubMedGoogle Scholar
  33. 33.
    Sempowski GD, Cross SJ, Heinly CS, Scearce RM, Haynes BF (2004) CD7 and CD28 are required for murine CD4+CD25+ regulatory T cell homeostasis and prevention of thyroiditis. J Immunol 172:787PubMedGoogle Scholar
  34. 34.
    Picca CC, Caton AJ (2005) The role of self-peptides in the development of CD4+ CD25+ regulatory T cells. Curr Opin Immunol 17:131PubMedGoogle Scholar
  35. 35.
    Shevach EM (2002) CD4+CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:389PubMedGoogle Scholar
  36. 36.
    Klein L, Khazaie K, von Boehmer H (2003) In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc Natl Acad Sci USA 100:8886PubMedGoogle Scholar
  37. 37.
    Walker LS, Chodos A, Eggena M, Dooms H, Abbas AK (2003) Antigen-dependent proliferation of CD4+CD25+ regulatory T cells in vivo. J Exp Med 198:249PubMedGoogle Scholar
  38. 38.
    Gavin MA, Clarke SR, Negrou E, Gallegos A, Rudensky A (2002) Homeostasis and anergy of CD4(+)CD25(+) suppressor T cells in vivo. Nat Immunol 3:33PubMedGoogle Scholar
  39. 39.
    Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa TC, Cumano A, Bandeira A (2001) CD25+CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol 166:3008PubMedGoogle Scholar
  40. 40.
    Scheinecker C, McHugh R, Shevach EM, Germain RN (2002) Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J Exp Med 196:1079PubMedGoogle Scholar
  41. 41.
    McHugh RS, Shevach EM (2002) Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J Immunol 168:5979PubMedGoogle Scholar
  42. 42.
    Kohm AP, Carpentier PA, Anger HA, Miller SD (2002) Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 169:4712PubMedGoogle Scholar
  43. 43.
    Verginis P, Li HS, Carayanniotis G (2005) Tolerogenic semimature dendritic cells suppress experimental autoimmune thyroiditis by activation of thyroglobulin-specific CD4+CD25+ T cells. J Immunol 174:7433PubMedGoogle Scholar
  44. 44.
    Liu R, La Cava A, Bai XF, Jee Y, Price M, Campagnolo DI, Christadoss P, Vollmer TL, Van Kaer L, Shi FD (2005) Cooperation of invariant NKT cells and CD4+CD25+ T regulatory cells in the prevention of autoimmune myasthenia. J Immunol 175:7898PubMedGoogle Scholar
  45. 45.
    DiPaolo RJ, Glass DD, Bijwaard KE, Shevach EM (2005) CD4+CD25+ T cells prevent the development of organ-specific autoimmune disease by inhibiting the differentiation of autoreactive effector T cells. J Immunol 175:7135PubMedGoogle Scholar
  46. 46.
    Zwar TD, Read S, van Driel IR, Gleeson PA (2006) CD4+CD25+ regulatory T cells inhibit the antigen-dependent expansion of self-reactive T cells in vivo. J Immunol 176:1609PubMedGoogle Scholar
  47. 47.
    Suri-Payer E, Cantor H (2001) Differential cytokine requirements for regulation of autoimmune gastritis and colitis by CD4(+)CD25(+) T cells. J Autoimmun 16:115PubMedGoogle Scholar
  48. 48.
    McHugh, RS, Shevach EM, Thornton AM (2001) Control of organ-specific autoimmunity by immunoregulatory CD4(+)CD25(+) T cells. Microbes Infect 3:919PubMedGoogle Scholar
  49. 49.
    Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, Shevach EM (2002) CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 196:237PubMedGoogle Scholar
  50. 50.
    Stephens GL, McHugh RS, Whitters MJ, Young DA, Luxenberg D, Carreno BM, Collins M, Shevach EM (2004) Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol 173:5008PubMedGoogle Scholar
  51. 51.
    Seddon B, Mason D (1999) Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J Exp Med 189:877PubMedGoogle Scholar
  52. 52.
    Setiady YY, Agersborg S, Samy ET, Lewis JE, Tung KS (2005) Neonatal autoimmune disease: influence of CD4+CD25+ regulatory T cells. Int Rev Immunol 24:227PubMedGoogle Scholar
  53. 53.
    Samy ET, Parker LA, Sharp CP, Tung KS (2005) Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+CD25+ regulatory T cells in the regional lymph node. J Exp Med 202:771PubMedGoogle Scholar
  54. 54.
    Coombes JL, Robinson NJ, Maloy KJ, Uhlig HH, Powrie F (2005) Regulatory T cells and intestinal homeostasis. Immunol Rev 204:184PubMedGoogle Scholar
  55. 55.
    Faubion WA, De Jong YP, Molina AA, Ji H, Clarke K, Wang B, Mizoguchi E, Simpson SJ, Bhan AK, Terhorst C (2004) Colitis is associated with thymic destruction attenuating CD4+25+ regulatory T cells in the periphery. Gastroenterology 126:1759PubMedGoogle Scholar
  56. 56.
    Olson TS, Bamias G, Naganuma M, Rivera-Nieves J, Burcin TL, Ross W, Morris MA, Pizarro TT, Ernst PB, Cominelli F, Ley K (2004) Expanded B cell population blocks regulatory T cells and exacerbates ileitis in a murine model of Crohn disease. J Clin Invest 114:389PubMedGoogle Scholar
  57. 57.
    Mottet C, Uhlig HH, Powrie F (2003) Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 170:3939PubMedGoogle Scholar
  58. 58.
    Liu H, Hu B, Xu D, Liew FY (2003) CD4+CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-beta, and CTLA4. J Immunol 171:5012PubMedGoogle Scholar
  59. 59.
    Erdman SE, Poutahidis T, Tomczak M, Rogers AB, Cormier K, Plank B, Horwitz BH, Fox JG (2003) CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice. Am J Pathol 162:691PubMedGoogle Scholar
  60. 60.
    Annacker O, Coombes JL, Malmstrom V, Uhlig HH, Bourne T, Johansson-Lindbom B, Agace WW, Parker CM, Powrie F (2005) Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J Exp Med 202:1051PubMedGoogle Scholar
  61. 61.
    Denning TL, Kim G, Kronenberg M (2005) Cutting edge: CD4+CD25+ regulatory T cells impaired for intestinal homing can prevent colitis. J Immunol 174:7487PubMedGoogle Scholar
  62. 62.
    Asseman C, Read S, Powrie F (2003) Colitogenic Th1 cells are present in the antigen-experienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10. J Immunol 171:971PubMedGoogle Scholar
  63. 63.
    Kullberg MC, Hay V, Cheever AW, Mamura M, Sher A, Letterio JJ, Shevach EM, Piccirillo CA (2005) TGF-beta1 production by CD4+CD25+ regulatory T cells is not essential for suppression of intestinal inflammation. Eur J Immunol 35:2886PubMedGoogle Scholar
  64. 64.
    Fahlen L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA, Powrie F (2005) T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med 201:737PubMedGoogle Scholar
  65. 65.
    Peng Y, Laouar Y, Li MO, Green EA, Flavell RA (2004) TGF-beta egulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci USA 101:4572PubMedGoogle Scholar
  66. 66.
    Wahl SM, Swisher J, McCartney-Francis N, Chen W (2004) TGF-beta: the perpetrator of immune suppression by regulatory T cells and suicidal T cells. J Leukoc Biol 76:15PubMedGoogle Scholar
  67. 67.
    Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875PubMedGoogle Scholar
  68. 68.
    Liu Z, Geboes K, Hellings P, Maerten P, Heremans H, Vandenberghe P, Boon L, van Kooten P, Rutgeerts P, Ceuppens JL (2001) B7 interactions with CD28 and CTLA-4 control tolerance or induction of mucosal inflammation in chronic experimental colitis. J Immunol 167:1830PubMedGoogle Scholar
  69. 69.
    de Jong YP, Rietdijk ST, Faubion WA, Abadia-Molina AC, Clarke K, Mizoguchi E, Tian J, Delaney T, Manning S, Gutierrez-Ramos JC, Bhan AK, Coyle AJ, Terhorst C (2004) Blocking inducible co-stimulator in the absence of CD28 impairs Th1 and CD25+ regulatory T cells in murine colitis. Int Immunol 16:205PubMedGoogle Scholar
  70. 70.
    Annacker O, Burlen-Defranoux O, Pimenta-Araujo R, Cumano A, Bandeira A (2000) Regulatory CD4 T cells control the size of the peripheral activated/memory CD4 T cell compartment. J Immunol 164:3573PubMedGoogle Scholar
  71. 71.
    Gad M, Pedersen AE, Kristensen NN, Claesson MH (2004) Demonstration of strong enterobacterial reactivity of CD4+CD25− T cells from conventional and germ-free mice which is counter-regulated by CD4+CD25+ T cells. Eur J Immunol 34:695PubMedGoogle Scholar
  72. 72.
    Martin B, Banz A, Bienvenu B, Cordier C, Dautigny N, Becourt C, Lucas B (2004) Suppression of CD4+ T lymphocyte effector functions by CD4+CD25+ cells in vivo. J Immunol 172:3391PubMedGoogle Scholar
  73. 73.
    Furtado GC, Olivares-Villagomez D, Curotto de Lafaille MA, Wensky AK, Latkowski JA, Lafaille JJ (2001) Regulatory T cells in spontaneous autoimmune encephalomyelitis. Immunol Rev 182:122PubMedGoogle Scholar
  74. 74.
    Hori S, Haury M, Coutinho A, Demengeot J (2002) Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice. Proc Natl Acad Sci USA 99:8213PubMedGoogle Scholar
  75. 75.
    Gonzalez A, Andre-Schmutz I, Carnaud C, Mathis D, Benoist C (2001) Damage control, rather than unresponsiveness, effected by protective DX5+ T cells in autoimmune diabetes. Nat Immunol 2:1117PubMedGoogle Scholar
  76. 76.
    Zelenay S, Lopes-Carvalho T, Caramalho I, Moraes-Fontes MF, Rebelo M, Demengeot J (2005) Foxp3+ CD25− CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion. Proc Natl Acad Sci USA 102:4091PubMedGoogle Scholar
  77. 77.
    Hori S, Haury M, Lafaille JJ, Demengeot J, Coutinho A (2002) Peripheral expansion of thymus-derived regulatory cells in anti-myelin basic protein T cell receptor transgenic mice. Eur J Immunol 32:3729PubMedGoogle Scholar
  78. 78.
    McGeachy MJ, Stephens LA, Anderton SM (2005) Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system. J Immunol 175:3025PubMedGoogle Scholar
  79. 79.
    Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942PubMedGoogle Scholar
  80. 80.
    Yu P, Gregg RK, Bell JJ, Ellis JS, Divekar R, Lee HH, Jain R, Waldner H, Hardaway JC, Collins M, Kuchroo VK, Zaghouani H (2005) Specific T regulatory cells display broad suppressive functions against experimental allergic encephalomyelitis upon activation with cognate antigen. J Immunol 174:6772PubMedGoogle Scholar
  81. 81.
    Stephens LA, Gray D, Anderton SM (2005) CD4+CD25+ regulatory T cells limit the risk of autoimmune disease arising from T cell receptor crossreactivity. Proc Natl Acad Sci USA 102:17418PubMedGoogle Scholar
  82. 82.
    Zhang X, Koldzic DN, Izikson L, Reddy J, Nazareno RF, Sakaguchi S, Kuchroo VK, Weiner HL (2004) IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells. Int Immunol 16:249PubMedGoogle Scholar
  83. 83.
    Reddy J, Illes Z, Zhang X, Encinas J, Pyrdol J, Nicholson L, Sobel RA, Wucherpfennig KW, Kuchroo VK (2004) Myelin proteolipid protein-specific CD4+CD25+ regulatory cells mediate genetic resistance to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 101:15434PubMedGoogle Scholar
  84. 84.
    Kohm AP, Williams JS, Miller SD (2004) Cutting edge: ligation of the glucocorticoid-induced TNF receptor enhances autoreactive CD4+ T cell activation and experimental autoimmune encephalomyelitis. J Immunol 172:4686PubMedGoogle Scholar
  85. 85.
    Zhang, X, Reddy J, Ochi H FD, Kuchroo VK, Weiner HL (2006) Recovery from experimental allergic encephalomyelitis is TGFb dependent and associated with increases in CD4+LAP+ and CD4+CD25+ T cells. Int Immunol 18:495–503PubMedGoogle Scholar
  86. 86.
    Fernandez-Martin A, Gonzalez-Rey E, Chorny A, Ganea D, Delgado M (2006) Vasoactive intestinal peptide induces regulatory T cells during experimental autoimmune encephalomyelitis. Eur J Immunol 36:318PubMedGoogle Scholar
  87. 87.
    Duplan V, Beriou G, Heslan JM, Bruand C, Dutartre P, Mars LT, Liblau RS, Cuturi MC, Saoudi A (2006) LF 15-0195 treatment protects against central nervous system autoimmunity by favoring the development of Foxp3-expressing regulatory CD4 T cells. J Immunol 176:839PubMedGoogle Scholar
  88. 88.
    Beyersdorf N, Gaupp S, Balbach K, Schmidt J, Toyka KV, Lin CH, Hanke T, Hunig T, Kerkau T, Gold R (2005) Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis. J Exp Med 202:445PubMedGoogle Scholar
  89. 89.
    Anderson MS, Bluestone JA (2005) The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23:447PubMedGoogle Scholar
  90. 90.
    Piccirillo CA, Tritt M, Sgouroudis E, Albanese A, Pyzik M, Hay V (2005) Control of type 1 autoimmune diabetes by naturally occurring CD4+CD25+ regulatory T lymphocytes in neonatal NOD mice. Ann NY Acad Sci 1051:72PubMedGoogle Scholar
  91. 91.
    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 12:431PubMedGoogle Scholar
  92. 92.
    Green EA, Choi Y, Flavell RA (2002) Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity 16:183PubMedGoogle Scholar
  93. 93.
    Berzins SP, Venanzi ES, Benoist C, Mathis D (2003) T-cell compartments of prediabetic NOD mice. Diabetes 52:327PubMedGoogle Scholar
  94. 94.
    Pop SM, Wong CP, Culton DA, Clarke SH, Tisch R (2005) Single cell analysis shows decreasing FoxP3 and TGFbeta1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes. J Exp Med 201:1333PubMedGoogle Scholar
  95. 95.
    Chen Z, Herman AE, Matos M, Mathis D, Benoist C (2005) Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. J Exp Med 202:1387PubMedGoogle Scholar
  96. 96.
    Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, Santamaria P, Locksley RM, Krummel MF, Bluestone JA (2006) Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 7:83PubMedGoogle Scholar
  97. 97.
    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 199:1479PubMedGoogle Scholar
  98. 98.
    Serra P, Amrani A, Yamanouchi J, Han B, Thiessen S, Utsugi T, Verdaguer J, Santamaria P (2003) CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 19:877PubMedGoogle Scholar
  99. 99.
    Bruder D, Westendorf AM, Hansen W, Prettin S, Gruber AD, Qian Y, von Boehmer H, Mahnke K, Buer J (2005) On the edge of autoimmunity: T-cell stimulation by steady-state dendritic cells prevents autoimmune diabetes. Diabetes 54:3395PubMedGoogle Scholar
  100. 100.
    Masteller EL, Warner MR, Tang Q, Tarbell KV, McDevitt H, Bluestone JA (2005) Expansion of functional endogenous antigen-specific CD4+CD25+ regulatory T cells from nonobese diabetic mice. J Immunol 175:3053PubMedGoogle Scholar
  101. 101.
    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 199:1455PubMedGoogle Scholar
  102. 102.
    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 199:1467PubMedGoogle Scholar
  103. 103.
    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 169:2461PubMedGoogle Scholar
  104. 104.
    Goudy KS, Burkhardt BR, Wasserfall C, Song S, Campbell-Thompson ML, Brusko T, Powers MA, Clare-Salzler MJ, Sobel ES, Ellis TM, Flotte TR, Atkinson MA (2003) Systemic overexpression of IL-10 induces CD4+CD25+ cell populations in vivo and ameliorates type 1 diabetes in nonobese diabetic mice in a dose-dependent fashion. J Immunol 171:2270PubMedGoogle Scholar
  105. 105.
    Luo X, Yang H, Kim IS, Saint-Hilaire F, Thomas DA, De BP, Ozkaynak E, Muthukumar T, Hancock WW, Crystal RG, Suthanthiran M (2005) Systemic transforming growth factor-beta1 gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice. Transplantation 79:1091PubMedGoogle Scholar
  106. 106.
    Bagavant H, Tung KS (2005) Failure of CD25+ T cells from lupus-prone mice to suppress lupus glomerulonephritis and sialoadenitis. J Immunol 175:944PubMedGoogle Scholar
  107. 107.
    Lim HW, Hillsamer P, Banham AH, Kim CH (2005) Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J Immunol 175:4180PubMedGoogle Scholar
  108. 108.
    Bystry RS, Aluvihare V, Welch KA, Kallikourdis M, Betz AG (2001) B cells and professional APCs recruit regulatory T cells via CCL4. Nat Immunol 2:1126PubMedGoogle Scholar
  109. 109.
    Fields ML, Hondowicz BD, Metzgar MH, Nish SA, Wharton GN, Picca CC, Caton AJ, Erikson J (2005) CD4+CD25+ regulatory T cells inhibit the maturation but not the initiation of an autoantibody response. J Immunol 175:4255PubMedGoogle Scholar
  110. 110.
    Zhao DM, Thornton AM, Dipaolo RJ, Shevach EM (2006) Activated CD4+CD25+ T cells selectively kill B lymphocytes. BloodGoogle Scholar
  111. 111.
    Monk CR, Spachidou M, Rovis F, Leung E, Botto M, Lechler RI, Garden OA (2005) MRL/Mp CD4+,CD25- T cells show reduced sensitivity to suppression by CD4+, CD25+ regulatory T cells in vitro: a novel defect of T cell regulation in systemic lupus erythematosus. Arthritis Rheum 52:1180PubMedGoogle Scholar
  112. 112.
    Morgan ME, Sutmuller RP, Witteveen HJ, van Duivenvoorde LM, Zanelli E, Melief CJ, Snijders A, Offringa R, de Vries RR, Toes RE (2003) CD25+ cell depletion hastens the onset of severe disease in collagen-induced arthritis. Arthritis Rheum 48:1452PubMedGoogle Scholar
  113. 113.
    Morgan ME, Flierman R, van Duivenvoorde LM, Witteveen HJ, van Ewijk W, van Laar JM, de Vries RR, Toes RE (2005) Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum 52:2212PubMedGoogle Scholar
  114. 114.
    Maloy KJ, Antonelli LR, Lefevre M, Powrie F (2005) Cure of innate intestinal immune pathology by CD4+CD25+ regulatory T cells. Immunol Lett 97:189PubMedGoogle Scholar
  115. 115.
    Siegmund K, Feuerer M, Siewert C, Ghani S, Haubold U, Dankof A, Krenn V, Schon MP, Scheffold A, Lowe JB, Hamann A, Syrbe U, Huehn J (2005) Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo. Blood 106:3097PubMedGoogle Scholar
  116. 116.
    Lee I, Wang L, Wells AD, Dorf ME, Ozkaynak E, Hancock WW (2005) Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J Exp Med 201:1037PubMedGoogle Scholar
  117. 117.
    Piccirillo CA, Shevach EM (2001) Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J Immunol 167:1137PubMedGoogle Scholar
  118. 118.
    Gondek DC, Lu LF, Quezada SA, Sakaguchi S, Noelle RJ (2005) Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 174:1783PubMedGoogle Scholar
  119. 119.
    Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N, Puig PE, Novault S, Escudier B, Vivier E, Lecesne A, Robert C, Blay JY, Bernard J, Caillat-Zucman S, Freitas A, Tursz T, Wagner-Ballon O, Capron C, Vainchencker W, Martin F, Zitvogel L (2005) CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 202:1075PubMedGoogle Scholar
  120. 120.
    Azuma T, Takahashi T, Kunisato A, Kitamura T, Hirai H (2003) Human CD4+ CD25+ regulatory T cells suppress NKT cell functions. Cancer Res 63:4516PubMedGoogle Scholar
  121. 121.
    Taams LS, van Amelsfort JM, Tiemessen MM, Jacobs KM, de Jong EC, Akbar AN, Bijlsma JW, Lafeber FP (2005) Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum Immunol 66:222PubMedGoogle Scholar
  122. 122.
    Chen ML, Pittet MJ, Gorelik L, Flavell RA, Weissleder R, von Boehmer H, Khazaie K (2005) Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA 102:419PubMedGoogle Scholar
  123. 123.
    Maloy KJ, Salaun L, Cahill R, Dougan G, Saunders NJ, Powrie F (2003) CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J Exp Med 197:111PubMedGoogle Scholar
  124. 124.
    Min WP, Zhou D, Ichim TE, Strejan GH, Xia X, Yang J, Huang X, Garcia B, White D, Dutartre P, Jevnikar AM, Zhong R (2003) Inhibitory feedback loop between tolerogenic dendritic cells and regulatory T cells in transplant tolerance. J Immunol 170:1304PubMedGoogle Scholar
  125. 125.
    Misra N, Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV (2004) Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol 172:4676PubMedGoogle Scholar
  126. 126.
    Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY (2004) Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21:267PubMedGoogle Scholar
  127. 127.
    Lafaille JJ, Nagashima K, Katsuki M, Tonegawa S (1994) High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice. Cell 78:399PubMedGoogle Scholar
  128. 128.
    Takeda I, Ine S, Killeen N, Ndhlovu LC, Murata K, Satomi S, Sugamura K, Ishii N (2004) Distinct roles for the OX40-OX40 ligand interaction in regulatory and nonregulatory T cells. J Immunol 172:3580PubMedGoogle Scholar
  129. 129.
    Pasare C, Medzhitov R (2004) Toll-dependent control mechanisms of CD4 T cell activation. Immunity 21:733PubMedGoogle Scholar
  130. 130.
    King IL, Segal BM (2005) Cutting edge: IL-12 induces CD4+CD25- T cell activation in the presence of T regulatory cells. J Immunol 175:641PubMedGoogle Scholar
  131. 131.
    Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J (2003) Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197:403PubMedGoogle Scholar
  132. 132.
    Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ, Joosten LA, Akira S, Netea MG, Adema GJ (2006) Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 116:485PubMedGoogle Scholar
  133. 133.
    Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang RF (2005) Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309:1380PubMedGoogle Scholar
  134. 134.
    Crellin NK, Garcia RV, Hadisfar O, Allan SE, Steiner TS, Levings MK (2005) Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J Immunol 175:8051PubMedGoogle Scholar
  135. 135.
    Battaglia M, Gregori S, Bacchetta R, Roncarolo MG (2006) Tr1 cells: From discovery to their clinical application. Semin Immunol 18:120PubMedGoogle Scholar
  136. 136.
    Weiner HL (2001) Oral tolerance: immune mechanisms and the generation of Th3-type TGF-beta-secreting regulatory cells. Microbes Infect 3:947PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Department of NeonatologyUniversity of Heidelberg, Children’s HospitalHeidelbergGermany
  2. 2.Division of Immunogenetics, D030German Cancer Research CenterHeidelbergGermany

Personalised recommendations