FOXP3 and Its Role in the Immune System

  • Chang H. Kim
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 665)


FOXP3 is a member of the forkhead transcription factor family. Unlike other members, it is mainly expressed in a subset ofCD4+ T-cells that play a suppressive role in the immune system. A function of FOXP3 is to suppress the function of NFAT and NFKB and this leads to suppression of expression of many genes including IL-2 and effector T-cell cytokines. FOXP3 acts also as a transcription activator for many genes including CD25, Cytotoxic T-Lymphocyte Antigen4 (CTLA4), glucocorticoid-induced TNF receptor family gene (GITR) and folate receptor 4. FOXP3+ T-cells are made in the thymus and periphery. The FOXP3+ T-cells made in the thymus migrate to secondary lymphoid tissues and suppress antigen priming of lymphocytes. Antigen priming of naïve FOXP3+ T-cells and naïve FOXP3 T-cells leads to generation of memory FOXP3+ T-cells which are efficient in migration to nonlymphoid tissues. Memory FOXP3+ T-cells are, therefore, effective in suppression of effector T-cell function, while naive FOXP3+ T-cells are adept at suppressing the early immune responses in lymphoid tissues. Both naïve and memory FOXP3+ T-cells are required for effective maintenance of tolerance and prevention of autoimmune diseases throughout the body. Many factors such as cytokines and noncytokine factors regulate the generation of FOXP3+ T-cells. For example, retinoic acid, produced by the dendritic cells and epithelial cells in the intestine, works together with TGF-β1 and promotes generation of small intestine-homing FOXP3+ T-cells by upregulating the expression of FOXP3 and gut homing receptors. FOXP3+ T-cells can be produced in vitro from autologous naïve T-cells and, therefore, have great therapeutic potentials in treating a number of inflammatory diseases and graft rejection.


Retinoic Acid Experimental Autoimmune Encephalomyelitis Foxp3 Expression Forkhead Transcription Factor FOXP3 Gene 


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  1. 1.
    Bates GJ, Fox SB, Han C et al. Expression of the forkhead transcription factor FOXP1 is associated with that of estrogen receptor-beta in primary invasivebreast carcinomas. Breast Cancer Res Treat 2008; 111:453–459.PubMedGoogle Scholar
  2. 2.
    Campbell DJ, Ziegler SF. FOXP3 modifies the phenotypic and functional properties of regulatory T-cells. Nat Rev Immunol 2007; 7:305–310.PubMedGoogle Scholar
  3. 3.
    Shevach EM, DiPaolo RA, Andersson J et al. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T-cells. Immunol Rev 2006; 212:60–73.PubMedGoogle Scholar
  4. 4.
    Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol 2006; 24:209–226.PubMedGoogle Scholar
  5. 5.
    Kim CH. Molecular targets of FoxP3+ regulatory T-cells. Mini Rev Med Chern 2007; 7:1136–1143.Google Scholar
  6. 6.
    Sakaguchi S, Ono M, Setoguchi R et al. Foxp3+ CD25+ CD4+ natural regulatory T-cells in dominant self-tolerance and autoimmune disease. Immunol Rev 2006; 212:8–27.PubMedGoogle Scholar
  7. 7.
    Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T-cells in immunological tolerance to self and nonself. Nat Immunol 2005; 6:345–352.PubMedGoogle Scholar
  8. 8.
    Beyer M, Schultze JL. Regulatory T-cells in cancer. Blood 2006; 108:804–811.PubMedGoogle Scholar
  9. 9.
    Chang X, Gao JX, Jiang Q et al. The Scurfy mutation of FoxP3 in the thymus stroma leads to defective thyrnopoiesis. J Exp Med 2005; 2002:1141–1151.Google Scholar
  10. 10.
    Zuo T, Wang L, Morrison C et al. FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell 2007; 129:1275–1286.PubMedGoogle Scholar
  11. 11.
    Bennett CL, Yoshioka R, Kiyosawa H et al. X-Linked syndrome of polyendocrinopathy, immune dysfunction and diarrhea maps to Xp11.23–Xq13.3. Am J Hum Genet 2000; 66:461–468.PubMedGoogle Scholar
  12. 12.
    Bennett CL, Christie J, Ramsdell F et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27:20–21.PubMedGoogle Scholar
  13. 13.
    Kaufmann E, Muller D, Knochel W. DNA recognition site analysis of Xenopus winged helix proteins. J Mol Biol 1995; 248:239–254.PubMedGoogle Scholar
  14. 14.
    Schubert LA, Jeffery E, Zhang Y et al. Scurfin (FOXP3) acts as a repressor of transcription and regulates T-cell activation. J Biol Chem 2001; 276:37672–37679.PubMedGoogle Scholar
  15. 15.
    Lopes JE, Torgerson TR, Schubert LA et al. Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J Immunol 2006; 177:3133–3142.PubMedGoogle Scholar
  16. 16.
    Bettelli E, Dastrange M, Oukka M. FOXP3 interacts with nuclear factor of activated T-cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci USA 2005; 102:5138–5143.PubMedGoogle Scholar
  17. 17.
    Kamine J, Elangovan B, Subramanian T et al. Identification of a cellular protein that specifically interacts with the essential cysteine region of the HIV-1 Tat transactivator. Virology 1996; 216:357–366.PubMedGoogle Scholar
  18. 18.
    Yang XJ. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res 2004; 32:959–976.PubMedGoogle Scholar
  19. 19.
    Bennett CL, Ochs HD. IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy and a variety of autoimmune phenomena. Curr Opin Pediatr 2001; 13:533–538.PubMedGoogle Scholar
  20. 20.
    Ochs HD, Gambineri E, Torgerson TR. IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol Res 2007; 38:112–121.PubMedGoogle Scholar
  21. 21.
    van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations in FOXP3. Clin Dev Immunol 2007; 2007:89017.PubMedGoogle Scholar
  22. 22.
    Chen, C, Rowell EA, Thomas RM et al. Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation. J Biol Chem 2006; 281:36828–36834.PubMedGoogle Scholar
  23. 23.
    Zheng Y, Josefowicz SZ, Kas A et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T-cells. Nature 2007; 445:936–940.PubMedGoogle Scholar
  24. 24.
    Marson A, Kretschmer K, Frampton GM et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 2007; 445:931–935.PubMedGoogle Scholar
  25. 25.
    Wu Y, Borde M, Heissmeyer V et al. FOXP3 controls regulatory T-cell function through cooperation with NFAT. Cell 2006; 126:375–387.PubMedGoogle Scholar
  26. 26.
    Kim CH. Migration and function of FoxP3+ regulatory T-cells in the hematolyrnphoid system. Exp Hematol 2006; 34:1033–1040.PubMedGoogle Scholar
  27. 27.
    Mantel PY, Ouaked N, Ruckert B et al. Molecular mechanisms underlying FOXP3 induction in human T-cells. J Immunol 2006; 176:3593–3602.PubMedGoogle Scholar
  28. 28.
    Bisikirska B, Colgan J, Luban J et al. TCR stimulation with modified anti-CD3 mAb expands CD8+ T-cell population and induces CD8+CD25+ Tregs. J Clin Invest 2005; 115:2904–2913.PubMedGoogle Scholar
  29. 29.
    Fontenot JD, Dooley JL, Farr AG et al. Developmental regulation of Foxp3 expression during ontogeny. J Exp Med 2005; 2002:901–906.Google Scholar
  30. 30.
    Kim CH. Trafficking of FoxP3+ regulatory T-cells: myths and facts. Arch Immunol Ther Exp (Warsz) 2007; 55:151–159.Google Scholar
  31. 31.
    Lee JH, Kang SG, Kim CH. FoxP3+ T-cells undergo conventional first switch to lymphoid tissue homing receptors in thymus but accelerated second switch to nonlymphoid tissue homing receptors in secondary lymphoid tissues. J Immunol 2007; 178:301–311.PubMedGoogle Scholar
  32. 32.
    Tuovinen H, Kekalainen E, Rossi LH et al. Cutting edge: human CD4-CD8-thyrnocytes express FOXP3 in the absence of a TCR. J Immunol 2008; 180:3651–3654.PubMedGoogle Scholar
  33. 33.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T-cell development by the transcription factor Foxp3. Science 2003; 299:1057–1061.PubMedGoogle Scholar
  34. 34.
    Khattri R, Cox T, Yasayko SA et al. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003; 4:337–342.PubMedGoogle Scholar
  35. 35.
    Allan SE, Passerini L, Bacchetta R et al. The role of 2 FOXP3 isoforms in the generation of human CD4 Tregs. J Clin Invest 2005; 115:3276–3284.PubMedGoogle Scholar
  36. 36.
    Sauer S, Bruno L, Hertweck A et al. T-cell receptor signaling controls Foxp3 expression via PI3K, Akt and mTOR. Proc Natl Acad Sci USA 2008; 105:7797–7802.PubMedGoogle Scholar
  37. 37.
    Zorn E, Nelson EA, Mohseni M et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T-cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 2006; 108:1571–1579.PubMedGoogle Scholar
  38. 38.
    Floess S, Freyer J, Siewert C et al. Epigenetic control of the foxp3 locus in regulatory T-cells. PLoS Biol 2007; 5:e38.PubMedGoogle Scholar
  39. 39.
    Kim HP, Leonard WJ. CREB/ATF-dependent T-cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 2007; 204:1543–1551.PubMedGoogle Scholar
  40. 40.
    Chen W, Jin W, Hardegen N et al. Conversion of peripheral CD4+CD25− naive T-cells to CD4+CD25+ regulatory T-cells by TGF-beta induction oftranscription factor Foxp3. J Exp Med 2003; 198:1875–1886.PubMedGoogle Scholar
  41. 41.
    Fantini MC, Becker C, Monteleone G et al. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25− T-cells through Foxp3 induction and down-regulation of Smad7. J Immunol 2004; 172:5149–5153.PubMedGoogle Scholar
  42. 42.
    Tone Y, Furuuchi K, Kojima Y et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol 2008; 9:194–202.PubMedGoogle Scholar
  43. 43.
    Baron U, Floess S, Wieczorek G et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T-cells from activated FOXP3(+) conventional T-cells. Eur J Immunol 2007; 37:2378–2389.PubMedGoogle Scholar
  44. 44.
    Janson PC, Winerdal ME, Marits P et al. FOXP3 promoter demethylation reveals the committed Treg population in humans. PLoS ONE 2008; 3:e1612.PubMedGoogle Scholar
  45. 45.
    Polansky JK, Kretschmer K, Freyer J et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol 2008; 38:1654–1663.PubMedGoogle Scholar
  46. 46.
    Yao Z, Kanno Y, Kerenyi M et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 2007; 109:4368–4375.PubMedGoogle Scholar
  47. 47.
    Takaki H, Ichiyama K, Koga K et al. STAT6 Inhibits TGF-betal-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. J Biol Chem 2008; 283:14955–14962.PubMedGoogle Scholar
  48. 48.
    Nishihara M, Ogura H, Ueda N et al. IL-6-gp130-STAT3 in T-cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int Immunol 2007; 19:695–702.PubMedGoogle Scholar
  49. 49.
    Veldhoen M, Hocking RJ, Atkins CJ et al. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T-cells. Immunity 2006; 24:179–189.PubMedGoogle Scholar
  50. 50.
    Samanta A, Li B, Song X et al. TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3. Proc Natl Acad Sci USA 2008; 105:14023–14027.PubMedGoogle Scholar
  51. 51.
    Michie SA, Streeter PR, Bolt PA et al. The human peripheral lymph node vascular addressin. An inducible endothelial antigen involved in lymphocyte homing. Am J Pathol 1993; 143:1688–1698.PubMedGoogle Scholar
  52. 52.
    Picker LJ, Michie SA, Rott LS et al. A unique phenotype of skin-associated lymphocytes in humans. Preferential expression of the HECA-452 epitope by benign and malignant T-cells at cutaneous sites. Am J Pathol 1990; 136:1053–1068.PubMedGoogle Scholar
  53. 53.
    Streeter PR, Rouse BT, Butcher EC. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripheral lymph nodes. J Cell Biol 1988; 107:1853–1862.PubMedGoogle Scholar
  54. 54.
    Forster R, Schubel A, Breitfeld D et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 1999; 99:23–33.PubMedGoogle Scholar
  55. 55.
    Stein JV, Rot A, Luo Y et al. The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T-Iymphocytes in peripheral lymph node high endothelial venules. J Exp Med 2000; 191:61–76.PubMedGoogle Scholar
  56. 56.
    Warnock RA, Campbell JJ, Dorf ME et al. The role of chemokines in the microenvironmental control of T versus B-cell arrest in Peyer’s patch high endothelial venules. J Exp Med 2000; 191:77–88.PubMedGoogle Scholar
  57. 57.
    Wurbel MA, Malissen M, Guy-Grand D et al. Impaired accumulation of antigen-specific CD8 lymphocytes in chemokine CCL25-deficient intestinal epithelium and lamina propria. J Immunol 2007; 178:7598–7606.PubMedGoogle Scholar
  58. 58.
    Wendland M, Czeloth N, Mach N et al. CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc Natl Acad Sci USA 2007; 104:6347–6352.PubMedGoogle Scholar
  59. 59.
    Stenstad H, Ericsson A, Johansson-Lindborn B et al. Gut-associated lymphoid tissue-primed CD4+ T-cells display CCR9-dependent and-independent homing to the small intestine. Blood 2006; 107:3447–3454.PubMedGoogle Scholar
  60. 60.
    Papadakis KA, Prehn J, Nelson V et al. The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system. J Immunol 2000; 165:5069–5076.PubMedGoogle Scholar
  61. 61.
    Kunkel EJ, Campbell JJ, Haraldsen G et al. Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J Exp Med 2000; 192:761–768.PubMedGoogle Scholar
  62. 62.
    Hamann A, Andrew DP, Jablonski-Westrich D et al. Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol 1994; 152:3282–3293.PubMedGoogle Scholar
  63. 63.
    Berlin C, Berg EL, Briskin MJ et al. Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 1993; 74:185–185.PubMedGoogle Scholar
  64. 64.
    Lim HW, Hillsamer P, Kim CH. Regulatory T-cells can migrate to follicles upon T-cell activation and suppress GC-Th cells and GC-Th cell-driven B-cell responses. J Clin Invest 2004; 114:1640–1649.PubMedGoogle Scholar
  65. 65.
    Huehn J, Siegmund K, Lehmann JC et al. Developmental Stage, Phenotype and Migration Distinguish Naive-and Effector/Memory-like CD4+ Regulatory T-Cells. J Exp Med 2004; 199:303–313.PubMedGoogle Scholar
  66. 66.
    Lee I, Wang L, Wells AD et al. Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J Exp Med 2005; 201:1037–1044.PubMedGoogle Scholar
  67. 67.
    Sather BD, Treuting P, Perdue N et al. Altering the distribution of Foxp3(+) regulatory T-cells results in tissue-specific inflammatory disease. J Exp Med 2007; 204:1335–1347.PubMedGoogle Scholar
  68. 68.
    Schneider MA, Meingassner JG, Lipp M et al. CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T-cells. J Exp Med 2007; 204:735–745.PubMedGoogle Scholar
  69. 69.
    Mucida D, Park Y, Kim G et al. Reciprocal TH17 and regulatory T-cell differentiation mediated by retinoic acid. Science 2007; 317:256–260.PubMedGoogle Scholar
  70. 70.
    Benson MJ, Pino-Lagos K, Rosemblatt M et al. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation and gut homing in the face of high levels of costimulation. J Exp Med 2007; 204:1765–1774.PubMedGoogle Scholar
  71. 71.
    Sun CM, Hall JA, Blank RB et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 2007; 204: 1775–1785.PubMedGoogle Scholar
  72. 72.
    Coombes JL, Siddiqui KR, Arancibia-Carcamo CV et al. A functionally specialized population of mucosal CDI03+ DCs induces Foxp3+ regulatory T-cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 2007; 204:1757–1764.PubMedGoogle Scholar
  73. 73.
    Kang SG, Lim HW, Andrisani OM et al. Vitamin A Metabolites Induce Gut-Homing FoxP3+ Regulatory T-Cells. J Immunol 2007; 179:3724–3733.PubMedGoogle Scholar
  74. 74.
    Schambach F, Schupp M, Lazar MA et al. Activation of retinoic acid receptor-alpha favours regulatory T-cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol 2007; 37:2396–2399.PubMedGoogle Scholar
  75. 75.
    Elias KM, Laurence A, Davidson TS et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/ Stat-5 independent signaling pathway. Blood 2008; 111:1013–1020.PubMedGoogle Scholar
  76. 76.
    Kim CH. Regulation of FoxP3 regulatory T-cells and Th17 cells by retinoids. Clin Dev Immunol 2008; 2008:416910.PubMedGoogle Scholar
  77. 77.
    Kang SG, Piniecki RJ, Hogenesch H et al. Identification of a chemokine network that recruits FoxP3(+) regulatory T-cells into chronically inAamed intestine. Gastroenterology 2007; 132:966–981.PubMedGoogle Scholar
  78. 78.
    Iwata M, Hirakiyama A, Eshima Y et al. Retinoic acid imprints gut-homing specificity on T-cells. Immunity 2004; 21:527–538.PubMedGoogle Scholar
  79. 79.
    Baumgart DC, Carding SR. In Aammatory bowel disease: cause and immunobiology. Lancet 2007; 369:1627–1640.PubMedGoogle Scholar
  80. 80.
    Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis and therapeutic opportunities. In Aamm Bowel Dis 2006; (12 Suppl 1):S3–9.Google Scholar
  81. 81.
    Xiao S, Jin H, Korn T et al. Retinoic acid increases Foxp3+ regulatory T-cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 2008; 181:2277–2284.PubMedGoogle Scholar
  82. 82.
    Suffia I, Reclding SK, Salay G et al. A role for CD 103 in the retention of CD4+CD25+ Treg and control of Leishmania major infection. J Immunol 2005; 174:5444–5455.PubMedGoogle Scholar
  83. 83.
    Annacker O, Coombes JL, Malmstrom V et al. Essential role for CDI03 in the T-cell-mediated regulation of experimental colitis. J Exp Med 2005; 202:1051–1061.PubMedGoogle Scholar
  84. 84.
    Ermann J, Hoffmann P, Edinger M et al. Only the CD62L+ subpopulation ofCD4+CD25+ regulatory T-cells protects from lethal acute GVHD. Blood 2005; 105:2220–2226.PubMedGoogle Scholar
  85. 85.
    Taylor PA, Panoskalrsis-Mortari A, Swedin JM et al. L-Selectin(hi) but not the L-selectin(lo) CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood 2004; 104:3804–3812.PubMedGoogle Scholar
  86. 86.
    Nakamura K, Kitani A, Strober W Cell contact-dependent immuno suppression by CD4(+)CD25(+) regulatory T-cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 2001; 194:629–644.PubMedGoogle Scholar
  87. 87.
    Piccirillo CA, Letterio JJ, Thornton AM et al. CD4(+)CD25(+) regulatory T-cells can mediate suppressor function in the absence of transforming growth factor beta I production and responsiveness. J Exp Med 2002; 196:237–246.PubMedGoogle Scholar
  88. 88.
    Mamura M, Lee W, Sullivan TJ et al. CD28 disruption exacerbates in Aammation in Tgf-betal-/-mice: in vivo suppression by CD4+CD25+ regulatory T-cells independent of autocrine TGF-beta1. Blood 2004; 103:4594–4601.PubMedGoogle Scholar
  89. 89.
    Huber S, Schramm C, Lehr HA et al. Cutting edge: TGF-beta signaling is required for the in vivo expansion and immuno suppressive capacity of regulatory CD4+CD25+ T-cells. J Immunol 2004; 173:6526–6531.PubMedGoogle Scholar
  90. 90.
    Nakamura K, Kitani A, Fuss I et al. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T-cell activity in both humans and mice. J Immunol 2004; 172:834–842.PubMedGoogle Scholar
  91. 91.
    Kullberg MC, Hay V, Cheever AW et al. TGF-beta1 production by CD4+ CD25+ regulatory T-cells is not essential for suppression of intestinal inflammation. Eur J Immunol 2005; 35:2886–2895.PubMedGoogle Scholar
  92. 92.
    Annunziato F, Cosmi L, Liotta F et al. Phenotype, localization and mechanism of suppressionof CD4(+) CD25(+) human thymocytes. J Exp Med 2002; 196:379–387.PubMedGoogle Scholar
  93. 93.
    Manzotti CN, Tipping H, Perry LC et al. Inhibition of human T-cell proliferation by CTLA-4 utilizes CD80 and requires CD25+ regulatory T-cells. Eur J Immunol 2002; 32:2888–2896.PubMedGoogle Scholar
  94. 94.
    Grohmann U, Orabona C, Fallarino F et al. CTLA-4-lg regulates tryptophan catabolism in vivo. Nat Immunol 2002; 3:1097–1101.PubMedGoogle Scholar
  95. 95.
    Grossman WJ, Verbsky W, Barchet W et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004; 21:589–601.PubMedGoogle Scholar
  96. 96.
    Gondek DC, Lu LF, Quezada SA et al. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 2005; 174:1783–1786.PubMedGoogle Scholar
  97. 97.
    Zhao DM, Thornton AM, DiPaolo RJ et al. Activated CD4+CD25+ T-cells selectively kill B-Iymphocytes. Blood 2006; 107:3925–3932.PubMedGoogle Scholar
  98. 98.
    Choi BM, Pae HO, Jeong YR et al. Critical role of heme oxygenase-l in Foxp3-mediated immune suppression. Biochem Biophys Res Commun 2005; 327:1066–1071.PubMedGoogle Scholar
  99. 99.
    Otterbein LE, Soares MP, Yamashita K et al. Heme oxygenase-l:unleashing the protective properties of heme. Trends Immunol 2003; 24:449–455.PubMedGoogle Scholar
  100. 100.
    Godfrey VL, Wilkinson JE, Rinchik EM et al. Fatallymphoreticular disease in the scurfy (sf) mouse requires T-cells that mature in a sf thymic environment: potential model for thymic education. Proc Natl Acad Sci USA 1991; 88:5528–5532.PubMedGoogle Scholar
  101. 101.
    Godfrey VL, Wilkinson JE, Russell LB. X-linked lymphoreticular disease in the scurfy (sf) mutant mouse. AmJ Pathol 1991; 138:1379–1387.Google Scholar
  102. 102.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T-cells. Nat Immunol 2003; 4:330–336.PubMedGoogle Scholar
  103. 103.
    Huter EN, Punkosdy GA, Glass DD et al. TGF-beta-induced Foxp3+ regulatory T-cells rescue scurfy mice. Eur J Immunol 2008; 38:1814–1821.PubMedGoogle Scholar
  104. 104.
    Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T-cells suppress polyclonal T-cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998; 188:287–296.PubMedGoogle Scholar
  105. 105.
    Piccirillo CA, Shevach EM. Cutting edge: control of CD8+ T-cell activation by CD4+CD25+ immunoregulatory cells. J Immunol 2001; 167:1137–1140.PubMedGoogle Scholar
  106. 106.
    Azuma T, Takahashi T, Kunisato A et al. Human CD4+ CD25+ regulatory T-cells suppress NKT cell functions. Cancer Res 2003; 63:4516–4520.PubMedGoogle Scholar
  107. 107.
    Taams LS, van Amelsfort JM, Tiemessen MM et al. Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T-cells. Hum Immunol 2005; 66:222–230.PubMedGoogle Scholar
  108. 108.
    Lim HW, Hillsamer P, Banham AH et al. Cutting Edge: Direct Suppression ofB-Cells by CD4+CD25+ Regulatory T-Cells. J Immunol 2005; 175:4180–4183.PubMedGoogle Scholar
  109. 109.
    Cederbom L, Hall H, Ivars F. CD4+CD25+ regulatory T-cells down-regulate costimulatory molecules on antigen-presenting cells. Eur J Immunol 2000; 30:1538–1543.PubMedGoogle Scholar
  110. 110.
    Smyth MJ, Teng MW, Swann J et al. CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J Immunol 2006; 176:1582–1587.PubMedGoogle Scholar
  111. 111.
    Salomon B, Lenschow DJ, Rhee L et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T-cells that control autoimmune diabetes. Immunity 2000; 12:431–440.PubMedGoogle Scholar
  112. 112.
    Kohm AP, Carpentier PA, Anger HA et al. 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 2002; 169:4712–4716.PubMedGoogle Scholar
  113. 113.
    Furtado GC, Olivares-Villagome ZD, Curotto de Lafaille MA et al. Regulatory T-cells in spontaneous autoimmune encephalomyelitis. Immunol Rev 2001; 182:122–134.PubMedGoogle Scholar
  114. 114.
    Sakaguchi S, Sakaguchi N, Asano M et al. Immunologic self-tolerance maintained by activated T-cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerancecauses various autoimmune diseases. J Immunol 1995; 155:1151–1164.PubMedGoogle Scholar
  115. 115.
    Singh B, Read S, Asseman C et al. Control of intestinal inflammation by regulatory T-cells. Immunol Rev 2001; 182:190–200.PubMedGoogle Scholar
  116. 116.
    Lee JH, Wang LC, Lin YT et al. Inverse correlation between CD4+ regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology 2006; 117:280–286.PubMedGoogle Scholar
  117. 117.
    Morgan ME, Sutmuller RP, Witteveen HJ et al. CD25+ cell depletion hastens the onset of severe disease in collagen-induced arthritis. Arthritis Rheum 2003; 48: 1452–1460.PubMedGoogle Scholar
  118. 118.
    Suri-Payer E, Amar AZ, Thornton AM et al. CD4+CD2S+ T-cells inhibit both the induction and effector function of autoreactive T-cells and represent a unique lineage of immunoregulatory cells. J Immunol 1998; 160:1212–1218.PubMedGoogle Scholar
  119. 119.
    Chen J, Huoam C, Plain K et al. CD4(+), CD2S(+) T-cells as regulators of alloimmune responses. Transplant Proc 2001; 33:163–164.PubMedGoogle Scholar
  120. 120.
    Wood KJ, Sakaguchi S. Regulatory T-cells in transplantation tolerance. Nat Rev Immunol 2003; 3:199–210.PubMedGoogle Scholar
  121. 121.
    Oluwole SF, Oluwole OO, DePaz HA et al. CD4+CD2S+ regulatory T-cells mediate acquired transplant tolerance. Transpl Immunol 2003; 11:287–293.PubMedGoogle Scholar
  122. 122.
    Belkaid Y, Piccirillo CA, Mendez S et al. CD4+CD2S+ regulatory T-cells control Leishmania major persistence and immunity. Nature 2002; 420:502–507.PubMedGoogle Scholar
  123. 123.
    Hori S, Carvalho TL, Demengeot J. CD2S+CD4+ regulatory T-cells suppress CD4+ T-cell-mediated pulmonary hyperinAammation driven by Pneumocystis carinii in immunodeficient mice. Eur J Immunol 2002; 32:1282–1291.PubMedGoogle Scholar
  124. 124.
    Rouse BT, Sarangi PP, Suvas S. Regulatory T-cells in virus infections. Immunol Rev 2006; 212:272–286.PubMedGoogle Scholar
  125. 125.
    Kullberg MC, Jankovic D, Gorelick PL et al. Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis. J Exp Med 2002; 196:505–515.PubMedGoogle Scholar
  126. 126.
    Kawaida H, Kono K, Takahashi A et al. Distribution of CD4+CD2Shigh regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. J Surg Res 2005; 124:151–157.PubMedGoogle Scholar
  127. 127.
    Woo EY, Chu CS, Goletz TJ et al. Regulatory CD4(+)CD2S(+) T-cells in tumors from patients with early-stage nonsmall cell lung cancer and late-stage ovarian cancer. Cancer Res 2001; 61:4766–4772.PubMedGoogle Scholar
  128. 128.
    Somasundaram R, Jacob L, Swoboda R et al. Inhibition of cytolytic T-Iymphocyte proliferation by autologous CD4+/CD2S+ regulatory T-cells in a colorectal carcinoma patient is mediated by transforming growth factor-beta. Cancer Res 2002; 62:5267–5272.PubMedGoogle Scholar
  129. 129.
    Liyanage UK, Moore TT, Joo HG et al. Prevalence of regulatory T-cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 2002; 169:2756–2761.PubMedGoogle Scholar
  130. 130.
    Ghiringhelli F, Larmonier N, Schmitt E et al. CD4+CD2S+ regulatory T-cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 2004; 34:336–344.PubMedGoogle Scholar
  131. 131.
    Fattorossi A, Battaglia A, Ferrandina G et al. Lymphocyte composition of tumor draining lymph nodes from cervical and endometrial cancer patients. Gynecol Oncol 2004; 92:106–115.PubMedGoogle Scholar
  132. 132.
    Sasada T, Kimura M, Yoshida Y et al. CD4+CD2S+ regulatory T-cells in patients with gastrointestinal malignancies: possible involvement of regulatory T-cells in disease progression. Cancer 2003; 98:1089–1099.PubMedGoogle Scholar
  133. 133.
    Schaefer C, Kim GG, Albers A et al. Characteristics of CD4+CD2S+ regulatory T-cells in the peripheral circulation of patients with head and neck cancer. Br J Cancer 2005; 92:913–920.PubMedGoogle Scholar
  134. 134.
    Unitt E, Rushbrook SM, Marshall A et al. Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 2005; 41:722–730.PubMedGoogle Scholar
  135. 135.
    Berger CL, Tigelaar R, Cohen J et al. Cutaneous T-cell lymphoma: malignant proliferation of T-regulatory cells. Blood 2005; 105:1640–1647.PubMedGoogle Scholar
  136. 136.
    Marshall NA, Christie LE, Munro LR et al. Immunosuppressive regulatory T-cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 2004; 103:1755–1762.PubMedGoogle Scholar
  137. 137.
    Beyer M, Kochanek M, Darabi K et al. Reduced frequencies and suppressive function of CD4+CD25hi regulatory T-cells in patients with chronic lymphocytic leukemia after therapy with Audarabine. Blood 2005; 106:2018–2025.PubMedGoogle Scholar
  138. 138.
    Chen GY, Chen C, Wang L et al. Cutting edge: Broad expression of the FoxP3 locus in epithelial cells: a caution against early interpretation of fatal inAammatory diseases following in vivo depletion of FoxP3-expressing cells. J Immunol 2008; 180:5163–5166.PubMedGoogle Scholar
  139. 139.
    Zuo T, Liu R, Zhang H et al. FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2. J Clin Invest 2007; 117:3765–3773.PubMedGoogle Scholar
  140. 140.
    Ebert LM, Tan BS, Browning J et al. The regulatory T-cell-associated transcription factor FoxP3 is expressed by tumor cells. Cancer Res 2008; 68:3001–3009.PubMedGoogle Scholar
  141. 141.
    Karanikas V, Speletas M, Zamanakou M et al. Foxp3 expression in human cancer cells. J Transl Med 2008; 6:19.PubMedGoogle Scholar
  142. 142.
    Yamaguchi T, Hirota K, Nagahama K et al. Control of immune responses by antigen-specific regulatory T-cells expressing the folate receptor. Immunity 2007; 27:145–159.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer+Business Media 2009

Authors and Affiliations

  • Chang H. Kim
    • 1
    • 2
  1. 1.Laboratory of Immunology and Hematopoiesis Department of Comparative Pathobiology Purdue Cancer CenterPurdue UniversityWest LafayetteUSA
  2. 2.Department of Comparative PathobiologyPurdue UniversityWest LafayetteUSA

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