Cancer Immunology, Immunotherapy

, Volume 53, Issue 2, pp 73–78 | Cite as

Anti-tumor immunity and autoimmunity: a balancing act of regulatory T cells

Symposium in Writing


Regulatory T (Treg) cell activity has been observed in anti-tumor and autoimmunity since the 1970s. Functional and molecular characterization of Treg cells has been made possible by the recent association of cell markers, such as CD25, CTLA-4, GITR, and Foxp3 gene product, with immunoregulatory activity. Here the influence of Treg cells in both anti-tumor immunity and autoimmunity was measured in BALB/c mice. Depletion of CD4+CD25+ Treg cells with CD25 mAb resulted in mammary tumor regression and increased susceptibility to thyroiditis. This in vivo priming to both tumor-associated antigens and self-thyroglobulin attests to the presence of otherwise undetectable immune effectors which are under negative regulation. Modulation of Treg cells is a powerful strategy in cancer therapy, but may potentiate autoimmune complications. Murine models exhibiting breakable tolerance to tumor-associated antigens, such as ErbB-2 (HER-2/neu), and increased susceptibility to autoimmunity following Treg-cell depletion are being established to test new vaccination or therapeutic strategies involving Treg-cell modulation.


  1. 1.
    Asherson G, Zembala M, Thomas W, Perera M (2003) Suppressor cells and the handling of antigen. Immunol Rev 50:3–45Google Scholar
  2. 2.
    Boggio K, Nicoletti G, Di Carlo E, Cavallo F, Landuzzi L, Melani C, Giovarelli M, Rossi I, Nanni P, De Giovanni C, Bouchard P, Wolf S, Modesti A, Musiani P, Lollini PL, Colombo MP, Forni G (1996) Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice. J Exp Med 188:589–596CrossRefGoogle Scholar
  3. 3.
    Calkins C, Stutman O (1978) Changes in suppressor mechanisms during postnatal development in mice. J Exp Med 147:87–97PubMedGoogle Scholar
  4. 4.
    Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J (2003) Regulatory T cells express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197:403–411PubMedGoogle Scholar
  5. 5.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3:991–998CrossRefPubMedGoogle Scholar
  6. 6.
    Ferrone S, Marincola FM (1995) Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinical relevance. Immunol Today 16:487–494PubMedGoogle Scholar
  7. 7.
    Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4(+)CD25(+) regulatory T cells. Nat Immunol 4:330–336PubMedGoogle Scholar
  8. 8.
    Fuller BE, Okayasu I, Simon LL, Giraldo AA, Kong YM (1993) Characterization of resistance to murine experimental autoimmune thyroiditis: duration and afferent action of thyroglobulin- and TSH-induced suppression. Clin Immunol Immunopathol 69:60–68PubMedGoogle Scholar
  9. 9.
    Gorelik L, Flavell RA (2001) Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med 7:1118–1122CrossRefPubMedGoogle Scholar
  10. 10.
    Higert I (1979) The involvement of activated specific suppressor T cells in maintenance of transplantation tolerance. Immunol Rev 46:27–53PubMedGoogle Scholar
  11. 11.
    Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061CrossRefPubMedGoogle Scholar
  12. 12.
    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: 5317–5326PubMedGoogle Scholar
  13. 13.
    Jones E, Dahm-Vicker M, Simon AK, Green A, Powrie F, Cerundolo V, Gallimore A (2002) Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun 2:1PubMedGoogle Scholar
  14. 14.
    Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4(+)CD25(+) T regulatory cells. Nat Immunol 4:337–342PubMedGoogle Scholar
  15. 15.
    Khong HT, Restifo NP (2002) Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat Immunol 3:999–1005CrossRefPubMedGoogle Scholar
  16. 16.
    Kojima A, Tanaka-Kojima Y, Sakakura T, Nishizuka Y (1976) Spontaneous development of autoimmune thyroiditis in neonatally thymectomized mice. Lab Invest 34:550–557PubMedGoogle Scholar
  17. 17.
    Kong YM (1999) Experimental models for autoimmune thyroid disease: recent developments. In: Volpe R (ed) Contemporary endocrinology: autoimmune endocrinopathies. Humana Press, Totowa, NJ, pp 91–111Google Scholar
  18. 18.
    Kong YM, Okayasu I, Giraldo AA, Beisel KW, Sundick RS, Rose NR, David CS, Audibert F, Chedid L (1982) Tolerance to thyroglobulin by activating suppressor mechanisms. Ann N Y Acad Sci 392:191–209PubMedGoogle Scholar
  19. 19.
    Kong YM, Giraldo AA, Waldmann H, Cobbold SP, Fuller BE (1989) Resistance to experimental autoimmune thyroiditis: L3T4+ cells as mediators of both thyroglobulin-activated and TSH-induced suppression. Clin Immunol Immunopathol 51:38–54PubMedGoogle Scholar
  20. 20.
    Levings MK, Sangregorio R, Sarukhan A, Moschin AL, Battaglia M, Orban P, Roncarolo M (2002) Human CD25+CD4+ T suppressor cell clones produce transforming growth factor beta, but not interleukin 10, and are distinct from type 1 T regulatory cells. J Exp Med 196:1335–1346PubMedGoogle Scholar
  21. 21.
    Lewis M, Giraldo AA, Kong YM (1987) Resistance to experimental autoimmune thyroiditis induced by physiologic manipulation of thyroglobulin level. Clin Immunol Immunopathol 45:92–104PubMedGoogle Scholar
  22. 22.
    Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, Drebin JA, Strasberg SM, Eberlein TJ, Goedegebuure PS, Linehan DC (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169:2756–2761PubMedGoogle Scholar
  23. 23.
    Mahoney KH, Miller BE, Heppner GH (1985) FACS quantitation of leucine aminopeptidase and acid phosphatase on tumor associated macrophages from metastatic and nonmetastatic mouse mammary tumors. J Leukoc Biol 38:573–585PubMedGoogle Scholar
  24. 24.
    Morris GP, Chen L, Kong YM (2003) CD137 signaling interferes with activation and function of regulatory CD4+CD25+ T cells in induced tolerance to experimental autoimmune thyroiditis (EAT). FASEB J 17:C258Google Scholar
  25. 25.
    Nabozny GH, Kong YM (1992) Circumvention of the induction of resistance in murine experimental autoimmune thyroiditis by recombinant IL-1β. J Immunol 149:1086–1092PubMedGoogle Scholar
  26. 26.
    Nocentini G, Giunchi L, Ronchetti S, Krausz LT, Bartoli A, Moraca R, Migliorati G, Riccardi C (2002) A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Proc Natl Acad Sci U S A 94:6216–6221CrossRefGoogle Scholar
  27. 27.
    Pekarek LA, Starr BA, Toledano AY, Schreiber H (1995) Inhibition of tumor growth by elimination of granulocytes. J Exp Med 181:435–440PubMedGoogle Scholar
  28. 28.
    Penhale WJ, Farmer A, Irvine WJ (1975) Thyroiditis in T cell-depleted rats: influence of strain, radiation dose, adjuvants and antilymphocyte serum. Clin Exp Immunol 21:362–375PubMedGoogle Scholar
  29. 29.
    Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, Restifo NP, Haworth LR, Seipp CA, Freezer LJ, Morton KE, Mavroukakis SA, Duray PH, Steinberg SM, Allison JP, Davis TA, Rosenberg SA (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100:8372–8377PubMedGoogle Scholar
  30. 30.
    Piechocki MP, Ho YS, Wei WZ (2001) Transgenic mice expressing human ErbB-2 (E2) under whey acidic protein promoter exhibit immunological tolerance to E2. Proc AACR 42:560Google Scholar
  31. 31.
    Piechocki MP, Pilon S, Wei W-Z (2001) Complementary antitumor immunity induced by plasmid DNA encoding secreted and cytoplasmic human ErbB-2. J Immunol 167:3367–3374PubMedGoogle Scholar
  32. 32.
    Piek E, Roberts AB (2001) Suppressor and oncogenic roles of transforming growth factor-beta and its signaling pathways in tumorigenesis. Adv Cancer Res 83:1–54PubMedGoogle Scholar
  33. 33.
    Pilon S, Piechocki MP, Wei W-Z (2001) Vaccination with cytoplasmic ErbB-2 DNA protects mice from mammary tumor growth without anti-ErbB-2 antibody. J Immunol 167:3201–3206PubMedGoogle Scholar
  34. 34.
    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 192:295–302CrossRefPubMedGoogle Scholar
  35. 35.
    Rovero S, Amici A, Di Carlo E, Bei R, Nanni P, Quaglino E, Porcedda P, Boggio K, Smorlesi A, Lollini PL, Landuzzi L, Colombo MP, Giovarelli M, Musiani P, Forni G (2000) Inhibition of carcinogenesis by DNA vaccination. J Immunol 165:5133–5142PubMedGoogle Scholar
  36. 36.
    Sakaguchi S (2003) Control of immune responses by naturally arising CD4+ regulatory T cells that express toll-like receptors. J Exp Med 197:397–401PubMedGoogle Scholar
  37. 37.
    Sakaguchi S, Fukuma K, Kuribayashi K, Masuda T (1985) 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 161:72–87PubMedGoogle Scholar
  38. 38.
    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 155:1151–1164PubMedGoogle Scholar
  39. 39.
    Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone J A (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12(4):431–440PubMedGoogle Scholar
  40. 40.
    Schatten S, Drebin JA, Perry LL, Chung W, Greene MI (1984) Regulation of the immune response to tumor antigens, X: activation of third-order suppressor T cells that abrogate anti-tumor immune responses. J Immunol 133:1064–1069PubMedGoogle Scholar
  41. 41.
    Schatten S, Granstein RD, Drebin JA, Greene MI (1984) Suppressor T cells and the immune response to tumors. Crit Rev Immunol 4:335–379PubMedGoogle Scholar
  42. 42.
    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 196:1079–1090PubMedGoogle Scholar
  43. 43.
    Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF (2001) Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 267:37672–37679CrossRefGoogle Scholar
  44. 44.
    Seliger B, Ritz U, Abele R, Bock M, Tampe R, Sutter G, Drexler I, Huber C, Ferrone S (2001) Immune escape of melanoma: first evidence of structural alterations in two distinct components of the MHC class I antigen processing pathway. Cancer Res 61:8647–8650PubMedGoogle Scholar
  45. 45.
    Shevach EM (2001) Certified professionals: CD4+ CD25+ suppressor T cells. J Exp Med 193:F41–F45PubMedGoogle Scholar
  46. 46.
    Shevach EM (2002) CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2:398–400Google Scholar
  47. 47.
    Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163(10), 5211–5218Google Scholar
  48. 48.
    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 3:135–142CrossRefGoogle Scholar
  49. 49.
    Spiotto MT, Yu P, Rowley DA, Nishimura MI, Meredith SC, Gajewski TF, Fu YX, Schreiber H (2002) Increasing tumor antigen expression overcomes “ignorance” to solid tumors via cross presentation by bone marrow-derived stromal cells. Immunity 17:737–747PubMedGoogle Scholar
  50. 50.
    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 192:303–309CrossRefPubMedGoogle Scholar
  51. 51.
    Thornton AM, Shevach EM (2000) Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 164:183–190PubMedGoogle Scholar
  52. 52.
    Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluesonte JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multi-organ tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–547PubMedGoogle Scholar
  53. 53.
    Ueda H, Howson J, Esposito L et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511PubMedGoogle Scholar
  54. 54.
    Vaidya B, Kendall-Taylor P, Pearce SHS (2002) Genetics of endocrine disease: the genetics of autoimmune thyroid disease. J Clin Endocrinol Metab 87:5385–5397PubMedGoogle Scholar
  55. 55.
    Vladutiu AO, Rose NR (1971) Autoimmune murine thyroiditis: relation to histocompatibility (H-2) type. Science 174:1137–1139PubMedGoogle Scholar
  56. 56.
    Volpé R (1990) Autoimmune diseases of the endocrine system. CRC Press, Boca Raton, pp 1–364Google Scholar
  57. 57.
    Wei WZ, Shi WP, Galy A, Lichlyter D, Hernandez S, Groner B, Heilbrun L, Jones RF (1999) Protection against mammary tumor growth by vaccination with full-length, modified human ErbB-2 DNA. Int J Cancer 81:748–754PubMedGoogle Scholar
  58. 58.
    Woo EY, Yeh H, Chu CS, Schlienger K, Carroll RG, Riley JL, Kaiser LR, June CH (2002) Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J Immunol 168:4272–4276PubMedGoogle Scholar
  59. 59.
    Young MR, Wright MA, Pandit R (1997) Myeloid differentiation treatment to diminish the presence of immune-suppressive CD34+ cells within human head and neck squamous cell carcinomas. J Immunol 159:990–996PubMedGoogle Scholar
  60. 60.
    Zhang W, Kong YM (1998) IL-12 interferes with tolerance induction to experimental autoimmune thyroiditis. Cell Immunol 208:52–61CrossRefPubMedGoogle Scholar
  61. 61.
    Zhang W, Kong YM (1998) Noninvolvement of IL-4 and IL-10 in tolerance induction to experimental autoimmune thyroiditis. Cell Immunol 187:95–102PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Wei-Zen Wei
    • 1
  • Gerald P. Morris
    • 1
  • Yi-chi M. Kong
    • 1
  1. 1.Karmanos Cancer Institute, Department of Immunology and MicrobiologyWayne State UniversityDetroitUSA

Personalised recommendations