468
Views
20
CrossRef citations to date
0
Altmetric
Review Article

Regulatory T cells—the renaissance of the suppressor T cells

, &
Pages 322-334 | Published online: 08 Jul 2009

References

  • Miller J. F. Immunological function of the thymus. Lancet 1961; 2: 748–9
  • Miller J. F., Mitchell G. F. Cell to cell interaction in the immune response. I. Hemolysin‐forming cells in neonatally thymectomized mice reconstituted with thymus or thoracic duct lymphocytes. J Exp Med 1968; 128: 801–20
  • Gershon R. K., Cohen P., Hencin R., Liebhaber S. A. Suppressor T cells. J Immunol 1972; 108: 586–90
  • Gershon R. K., Kondo K. Cell interactions in the induction of tolerance: the role of thymic lymphocytes. Immunology 1970; 18: 723–37
  • Gershon R. K. A disquisition on suppressor T cells. Transplant Rev 1975; 26: 170–85
  • Okumura K., Takemori T., Tokuhisa T., Tada T. Specific enrichment of the suppressor T cell bearing I‐J determinants: parallel functional and serological characterizations. J Exp Med 1977; 146: 1234–45
  • Tada T., Taniguchi M., David C. S. Properties of the antigen‐specific suppressive T‐cell factor in the regulation of antibody response of the mouse. IV. Special subregion assignment of the gene(s) that codes for the suppressive T‐cell factor in the H‐2 histocompatibility complex. J Exp Med 1976; 144: 713–25
  • Kronenberg M., Steinmetz M., Kobori J., Kraig E., Kapp J. A., Pierce C. W., et al. RNA transcripts for I‐J polypeptides are apparently not encoded between the I‐A and I‐E subregions of the murine major histocompatibility complex. Proc Natl Acad Sci U S A 1983; 80: 5704–8
  • Steinmetz M., Minard K., Horvath S., McNicholas J., Srelinger J., Wake C., et al. A molecular map of the immune response region from the major histocompatibility complex of the mouse. Nature 1982; 300: 35–42
  • 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 1995; 155: 1151–64
  • Thornton A. M., Shevach E. M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998; 188: 287–96
  • Khattri R., Cox T., Yasayko S. A., Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003; 4: 337–42
  • Schubert L. A., Jeffery E., Zhang Y., Ramsdell F., Ziegler S. F. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 2001; 276: 37672–9
  • Chatila T. A., Blaeser F., Ho N., Lederman H. M., Voulgaropoulos C., Helms C., et al. JM2, encoding a fork head‐related protein, is mutated in X‐linked autoimmunity‐allergic disregulation syndrome. J Clin Invest 2000; 106: R75–81
  • Brunkow M. E., Jeffery E. W., Hjerrild K. A., Paeper B., Clark L. B., Yasayko S. A., et al. Disruption of a new forkhead/winged‐helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001; 27: 68–73
  • Wildin R. S., Ramsdell F., Peake J., Faravelli F., Casanova J. L., Buist N., et al. X‐linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001; 27: 18–20
  • Bennett C. L., Christie J., Ramsdell F., Brunkow M. E., Ferguson P. J., Whitesell L., et al. The immune dysregulation, polyendocrinopathy, enteropathy, X‐linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001; 27: 20–1
  • Hori S., Nomura T., Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057–61
  • Fontenot J. D., Gavin M. A., Rudensky A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330–6
  • Walker M. R., Kasprowicz D. J., Gersuk V. H., Benard A., Van Landeghen M., Buckner J. H., et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+. J Clin Invest 2003; 112: 1437–43
  • Morgan M. E., van Bilsen J. H., Bakker A. M., Heemskerk B., Schilham M. W., Hartgers F. C., et al. Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum Immunol 2005; 66: 13–20
  • Allan S. E., Crome S. Q., Crellin N. K., Passerini L., Steiner T. S., Bacchetta R., et al. Activation‐induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 2007; 19: 345–54
  • Wang J., Ioan‐Facsinay A., van der Voort E. I., Huizinga T. W., Toes R. E. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 2007; 37: 129–38
  • Roncador G., Brown P. J., Maestre L., Hue S., Martinez‐Torrecuadrada J. L., Ling K. L., et al. Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T cells at the single‐cell level. Eur J Immunol 2005; 35: 1681–91
  • Yagi H., Nomura T., Nakamura K., Yamazaki S., Kitawaki T., Hori S., et al. Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol 2004; 16: 1643–56
  • Jordan M. S., Boesteanu A., Reed A. J., Petrone A. L., Holenbeck A. E., Lerman M. A., et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self‐peptide. Nat Immunol 2001; 2: 301–6
  • Chatenoud L., Bach J. F. Adaptive human regulatory T cells: myth or reality?. J Clin Invest 2006; 116: 2325–7
  • Roncarolo M. G., Bacchetta R., Bordignon C., Narula S., Levings M. K. Type 1 T regulatory cells. Immunol Rev 2001; 182: 68–79
  • Adorini L., Giarratana N., Penna G. Pharmacological induction of tolerogenic dendritic cells and regulatory T cells. Semin Immunol 2004; 16: 127–34
  • Chen Y., Kuchroo V. K., Inobe J., Hafler D. A., Weiner H. L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994; 265: 1237–40
  • Chen W., Jin W., Hardegen N., Lei K. J., Li L., Marinos N., et al. 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 2003; 198: 1875–86
  • Fantini M. C., Becker C., Monteleone G., Pallone F., Galle P. R., Neurath M. F. 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: 5149–53
  • Delgado M., Chorny A., Gonzalez‐Rey E., Ganea D. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. J Leukoc Biol 2005; 78: 1327–38
  • Fernandez‐Martin A., Gonzalez‐Rey E., Chorny A., Ganea D., Delgado M. Vasoactive intestinal peptide induces regulatory T cells during experimental autoimmune encephalomyelitis. Eur J Immunol 2006; 36: 318–26
  • Baratelli F., Lin Y., Zhu L., Yang S. C., Heuze‐Vourc'h N., Zeng G., et al. Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J Immunol 2005; 175: 1483–90
  • Jonuleit H., Schmitt E., Steinbrink K., Enk A. H. Dendritic cells as a tool to induce anergic and regulatory T cells. Trends Immunol 2001; 22: 394–400
  • Shevach E. M. CD4+ CD25+ suppressor T cells: more questions than answers. Nat Rev Immunol 2002; 2: 389–400
  • Thornton A. M., Shevach E. M. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 2000; 164: 183–90
  • Tang Q., Adams J. Y., Tooley A. J., Bi M., Fife B. T., Serra P., et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 2006; 7: 83–92
  • Jonuleit H., Schmitt E., Kakirman H., Stassen M., Knop J., Enk A. H. Infectious tolerance: human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells. J Exp Med 2002; 196: 255–60
  • Stassen M., Fondel S., Bopp T., Richter C., Muller C., Kubach J., et al. Human CD25+ regulatory T cells: two subsets defined by the integrins alpha 4 beta 7 or alpha 4 beta 1 confer distinct suppressive properties upon CD4+ T helper cells. Eur J Immunol 2004; 34: 1303–11
  • Nishizuka Y., Sakakura T. Thymus and reproduction: sex‐linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 1969; 166: 753–5
  • Powrie F. Immune regulation in the intestine: a balancing act between effector and regulatory T cell responses. Ann N Y Acad Sci 2004; 1029: 132–41
  • Annacker O., Asseman C., Read S., Powrie F. Interleukin‐10 in the regulation of T cell‐induced colitis. J Autoimmun 2003; 20: 277–9
  • Uhlig H. H., Coombes J., Mottet C., Izcue A., Thompson C., Fanger A., et al. Characterization of Foxp3+CD4+CD25+ and IL‐10‐Secreting CD4+CD25+ T Cells during Cure of Colitis. J Immunol 2006; 177: 5852–60
  • Kullberg M. C., Hay V., Cheever A. W., Mamura M., Sher A., Letterio J. J., et al. TGF‐beta1 production by CD4+ CD25+ regulatory T cells is not essential for suppression of intestinal inflammation. Eur J Immunol 2005; 35: 2886–95
  • Maloy K. J., Salaun L., Cahill R., Dougan G., Saunders N. J., Powrie F. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine‐dependent mechanisms. J Exp Med 2003; 197: 111–9
  • Fahlen L., Read S., Gorelik L., Hurst S. D., Coffman R. L., Flavell R. A., et al. T cells that cannot respond to TGF‐beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med 2005; 201: 737–46
  • Fantini M. C., Becker C., Tubbe I., Nikolaev A., Lehr H. A., Galle P., et al. Transforming growth factor beta induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut 2006; 55: 671–80
  • Makita S., Kanai T., Oshima S., Uraushihara K., Totsuka T., Sawada T., et al. CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol 2004; 173: 3119–30
  • Kelsen J., Agnholt J., Hoffmann H. J., Romer J. L., Hvas C. L., Dahlerup J. F. FoxP3(+)CD4(+)CD25(+) T cells with regulatory properties can be cultured from colonic mucosa of patients with Crohn's disease. Clin Exp Immunol 2005; 141: 549–57
  • Zamvil S. S., Steinman L. The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol 1990; 8: 579–621
  • Zhang X., Koldzic D. N., Izikson L., Reddy J., Nazareno R. F., Sakaguchi S., et al. IL‐10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells. Int Immunol 2004; 16: 249–56
  • Tisch R., McDevitt H. Insulin‐dependent diabetes mellitus. Cell. 1996; 85: 291–7
  • Delovitch T. L., Singh B. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 1997; 7: 727–38
  • King C., Sarvetnick N. Organ‐specific autoimmunity. Curr Opin Immunol 1997; 9: 863–71
  • Poulin M., Haskins K. Induction of diabetes in nonobese diabetic mice by Th2 T cell clones from a TCR transgenic mouse. J Immunol 2000; 164: 3072–8
  • Salomon B., Lenschow D. J., Rhee L., Ashourian N., Singh B., Sharpe A., et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 2000; 12: 431–40
  • Salomon B., Rhee L., Bour‐Jordan H., Hsin H., Montag A., Soliven B., et al. Development of spontaneous autoimmune peripheral polyneuropathy in B7‐2‐deficient NOD mice. J Exp Med 2001; 194: 677–84
  • Masteller E. L., Warner M. R., Tang Q., Tarbell K. V., McDevitt H., Bluestone J. A. Expansion of functional endogenous antigen‐specific CD4+CD25+ regulatory T cells from nonobese diabetic mice. J Immunol 2005; 175: 3053–9
  • Tarbell K. V., Yamazaki S., Olson K., Toy P., Steinman R. M. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 2004; 199: 1467–77
  • Every A. L., Kramer D. R., Mannering S. I., Lew A. M., Harrison L. C. Intranasal vaccination with proinsulin DNA induces regulatory CD4+ T cells that prevent experimental autoimmune diabetes. J Immunol 2006; 176: 4608–15
  • Bresson D., Togher L., Rodrigo E., Chen Y., Bluestone J. A., Herold K. C., et al. Anti‐CD3 and nasal proinsulin combination therapy enhances remission from recent‐onset autoimmune diabetes by inducing Tregs. J Clin Invest 2006; 116: 1371–81
  • Snell G. D., Higgins G. F. Alleles at the histocompatibility‐2 locus in the mouse as determined by tumor transplantation. Genetics 1951; 36: 306–10
  • Snell G. D. The genetics of transplantation. J Natl Cancer Inst. 1953; 14: 691–700
  • Billingham R. E., Brent L., Medawar P. B. Actively acquired tolerance of foreign cells. Nature 1953; 172: 603–6
  • Owen R. D. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 1945; 102: 400–01
  • Lance E. M., Medawar P. B. Survival of skin heterografts under treatment with antilymphocytic serum. Lancet 1968; 1: 1174–6
  • Gershon R. K., Kondo K. Infectious immunological tolerance. Immunology 1971; 21: 903–14
  • Hall B. M., Jelbart M. E., Gurley K. E., Dorsch S. E. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells. J Exp Med 1985; 162: 1683–94
  • Qin S., Cobbold S. P., Pope H., Elliott J., Kioussis D., Davies J., et al. “Infectious” transplantation tolerance. Science 1993; 259: 974–7
  • Waldmann H., Cobbold S. Regulating the immune response to transplants. A role for CD4+ regulatory cells?. Immunity 2001; 14: 399–406
  • Yin D., Fathman C. G. CD4‐positive suppressor cells block allotransplant rejection. J Immunol 1995; 154: 6339–45
  • Davies J. D., Martin G., Phillips J., Marshall S. E., Cobbold S. P., Waldmann H. T cell regulation in adult transplantation tolerance. J Immunol 1996; 157: 529–33
  • Honey K., Cobbold S. P., Waldmann H. CD40 ligand blockade induces CD4+ T cell tolerance and linked suppression. J Immunol 1999; 163: 4805–10
  • Arima T., Lehmann M., Flye M. W. Induction of donor specific transplantation tolerance to cardiac allografts following treatment with nondepleting (RIB 5/2) or depleting (OX‐38) anti‐CD4 mAb plus intrathymic or intravenous donor alloantigen. Transplantation 1997; 63: 284–92
  • Zhai Y., Shen X. D., Lehmann M., Busuttil R., Volk H. D., Kupiec‐Weglinski J. W. T cell subsets and in vitro immune regulation in “infectious” transplantation tolerance. J Immunol 2001; 167: 4814–20
  • Graca L., Cobbold S. P., Waldmann H. Identification of regulatory T cells in tolerated allografts. J Exp Med 2002; 195: 1641–6
  • Taylor P. A., Lees C. J., Blazar B. R. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft‐versus‐host disease lethality. Blood 2002; 99: 3493–9
  • Godfrey W. R., Spoden D. J., Ge Y. G., Baker S. R., Liu B., Levine B. L., et al. Cord blood CD4(+)CD25(+)‐derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function. Blood 2005; 105: 750–8
  • Tafuri A., Alferink J., Moller P., Hammerling G. J., Arnold B. T cell awareness of paternal alloantigens during pregnancy. Science 1995; 270: 630–3
  • Woodruff M. F. Transplantation immunity and the immunological problem of pregnancy. Proc R Soc Lond B Biol Sci 1958; 148: 68–75
  • Zenclussen A. C., Gerlof K., Zenclussen M. L., Sollwedel A., Bertoja A. Z., Ritter T., et al. Abnormal T‐cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy‐induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model. Am J Pathol 2005; 166: 811–22
  • Saito S., Sasaki Y., Sakai M. CD4(+)CD25high regulatory T cells in human pregnancy. J Reprod Immunol 2005; 65: 111–20
  • Sasaki Y., Sakai M., Miyazaki S., Higuma S., Shiozaki A., Saito S. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Hum Reprod 2004; 10: 347–53
  • Heikkinen J., Mottonen M., Alanen A., Lassila O. Phenotypic characterization of regulatory T cells in the human decidua. Clin Exp Immunol 2004; 136: 373–8
  • Somerset D. A., Zheng Y., Kilby M. D., Sansom D. M., Drayson M. T. Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T‐cell subset. Immunology 2004; 112: 38–43
  • Onizuka S., Tawara I., Shimizu J., Sakaguchi S., Fujita T., Nakayama E. Tumor rejection by in vivo administration of anti‐CD25 (interleukin‐2 receptor alpha) monoclonal antibody. Cancer Res 1999; 59: 3128–33
  • Sutmuller R. P., van Duivenvoorde L. M., van Elsas A., Schumacher T. N., Wildenberg M. E., Allison J. P., et al. Synergism of cytotoxic T lymphocyte‐associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001; 194: 823–32
  • Peng L., Kjaergaard J., Plautz G. E., Awad M., Drazba J. A., Shu S., et al. Tumor‐induced L‐selectinhigh suppressor T cells mediate potent effector T cell blockade and cause failure of otherwise curative adoptive immunotherapy. J Immunol 2002; 169: 4811–21
  • Gerlini G., Tun‐Kyi A., Dudli C., Burg G., Pimpinelli N., Nestle F. O. Metastatic melanoma secreted IL‐10 down‐regulates CD1 molecules on dendritic cells in metastatic tumor lesions. Am J Pathol 2004; 165: 1853–63
  • Van Belle P., Rodeck U., Nuamah I., Halpern A. C., Elder D. E. Melanoma‐associated expression of transforming growth factor‐beta isoforms. Am J Pathol 1996; 148: 1887–94
  • Curiel T. J., Coukos G., Zou L., Alvarez X., Cheng P., Mottram P., et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10: 942–9
  • Ko K., Yamazaki S., Nakamura K., Nishioka T., Hirota K., Yamaguchi T., et al. Treatment of advanced tumors with agonistic anti‐GITR mAb and its effects on tumor‐infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med 2005; 202: 885–91
  • Ghiringhelli F., Larmonier N., Schmitt E., Parcellier A., Cathelin D., Garrido C., et al. CD4+CD25+ 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: 336–44
  • Ercolini A. M., Ladle B. H., Manning E. A., Pfannenstiel L. W., Armstrong T. D., Machiels J. P., et al. Recruitment of latent pools of high‐avidity CD8(+) T cells to the antitumor immune response. J Exp Med 2005; 201: 1591–602
  • Fehleisen F. Über die Züchtung der Erysipelkokken auf künstlichem Nährboden und die Übertragbarkeit auf den Menschen. Dtsch Med Wochenschau 1882; 8: 553
  • Hobohm U. Fever and cancer in perspective. Cancer Immunol Immunother 2001; 50: 391–6
  • Busch W. Aus der Sitzung der medizinischen Sektion vom 13 November 1867. Berl Klin Wochenschr 1868; 5: 137
  • Coley W. B. A preliminary note on the treatment of inoperable sarcoma by the toxic product of erysipelas. Postgraduate 1893; 8: 278
  • Goldszmid R. S., Idoyaga J., Bravo A. I., Steinman R., Mordoh J., Wainstok R. Dendritic cells charged with apoptotic tumor cells induce long‐lived protective CD4+ and CD8+ T cell immunity against B16 melanoma. J Immunol 2003; 171: 5940–7
  • Rechtsteiner G., Warger T., Osterloh P., Schild H., Radsak M. P. Cutting edge: priming of CTL by transcutaneous peptide immunization with imiquimod. J Immunol 2005; 174: 2476–80
  • Warger T., Osterloh P., Rechtsteiner G., Fassbender M., Heib V., Schmid B., et al. Synergistic activation of dendritic cells by combined Toll‐like receptor ligation induces superior CTL responses in vivo. Blood 2006; 108: 544–50
  • Yang Y., Huang C. T., Huang X., Pardoll D. M. Persistent Toll‐like receptor signals are required for reversal of regulatory T cell‐mediated CD8 tolerance. Nat Immunol 2004; 5: 508–15
  • Rouse B. T., Suvas S. Regulatory cells and infectious agents: detentes cordiale and contraire. J Immunol 2004; 173: 2211–5
  • Suvas S., Azkur A. K., Kim B. S., Kumaraguru U., Rouse B. T. CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. J Immunol 2004; 172: 4123–32
  • Powrie F., Read S., Mottet C., Uhlig H., Maloy K. Control of immune pathology by regulatory T cells. Novartis Found Symp 2003; 252: 92–8
  • Mottet C., Uhlig H. H., Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 2003; 170: 3939–43
  • Belkaid Y., Piccirillo C. A., Mendez S., Shevach E. M., Sacks D. L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 2002; 420: 502–7
  • Yurchenko E., Tritt M., Hay V., Shevach E. M., Belkaid Y., Piccirillo C. A. CCR5‐dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistence. J Exp Med 2006; 203: 2451–60
  • Iwasaki A., Medzhitov R. Toll‐like receptor control of the adaptive immune responses. Nat Immunol 2004; 5: 987–95
  • Pasare C., Medzhitov R. Toll pathway‐dependent blockade of CD4+CD25+ T cell‐mediated suppression by dendritic cells. Science 2003; 299: 1033–6
  • Pasare C., Medzhitov R. Toll‐dependent control mechanisms of CD4 T cell activation. Immunity 2004; 21: 733–41
  • Thornton A. M., Donovan E. E., Piccirillo C. A., Shevach E. M. Cutting edge: IL‐2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol 2004; 172: 6519–23
  • Sutmuller R. P., den Brok M. H., Kramer M., Bennink E. J., Toonen L. W., Kullberg B. J., et al. Toll‐like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 2006; 116: 485–94
  • Stassen M., Jonuleit H., Muller C., Klein M., Richter C., Bopp T., et al. Differential regulatory capacity of CD25+ T regulatory cells and preactivated CD25+ T regulatory cells on development, functional activation, and proliferation of Th2 cells. J Immunol 2004; 267–74, 173
  • Zhao D. M., Thornton A. M., Dipaolo R. J., Shevach E. M. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood 2006; 107: 3925–32
  • Woo E. Y., Chu C. S., Goletz T. J., Schlienger K., Yeh H., Coukos G., et al. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early‐stage non‐small cell lung cancer and late‐stage ovarian cancer. Cancer Res 2001; 61: 4766–72
  • Wolf A. M., Wolf D., Steurer M., Gastl G., Gunsilius E., Grubeck‐Loebenstein B. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 2003; 9: 606–12
  • Antony P. A., Piccirillo C. A., Akpinarli A., Finkelstein S. E., Speiss P. J., Surman D. R., et al. CD8+ T cell immunity against a tumor/self‐antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol 2005; 174: 2591–601
  • Gray C. P., Arosio P., Hersey P. Association of increased levels of heavy‐chain ferritin with increased CD4+ CD25+ regulatory T‐cell levels in patients with melanoma. Clin Cancer Res 2003; 9: 2551–9
  • Enk A. H., Jonuleit H., Saloga J., Knop J. Dendritic cells as mediators of tumor‐induced tolerance in metastatic melanoma. Int J Cancer 1997; 73: 309–16
  • Rosenberg S. A. Shedding light on immunotherapy for cancer. N Engl J Med 2004; 350: 1461–3
  • O'Neill D. W., Adams S., Bhardwaj N. Manipulating dendritic cell biology for the active immunotherapy of cancer. Blood 2004; 104: 2235–46
  • Pasare C., Medzhitov R. Toll‐like receptors: balancing host resistance with immune tolerance. Curr Opin Immunol 2003; 15: 677–82
  • Viglietta V., Baecher‐Allan C., Weiner H. L., Hafler D. A. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 2004; 199: 971–9
  • Cao D., Malmstrom V., Baecher‐Allan C., Hafler D., Klareskog L., Trollmo C. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol 2003; 33: 215–23
  • Lindley S., Dayan C. M., Bishop A., Roep B. O., Peakman M., Tree T. I. Defective suppressor function in CD4(+)CD25(+) T‐cells from patients with type 1 diabetes. Diabetes 2005; 54: 92–9
  • Sugiyama H., Gyulai R., Toichi E., Garaczi E., Shimada S., Stevens S. R., et al. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 2005; 174: 164–73
  • Ehrenstein M. R., Evans J. G., Singh A., Moore S., Warnes G., Isenberg D. A., et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti‐TNFalpha therapy. J Exp Med 2004; 200: 277–85
  • Xystrakis E., Kusumakar S., Boswell S., Peek E., Urry Z., Richards D. F., et al. Reversing the defective induction of IL‐10‐secreting regulatory T cells in glucocorticoid‐resistant asthma patients. J Clin Invest 2006; 116: 146–55
  • Karagiannidis C., Akdis M., Holopainen P., Woolley N. J., Hense G., Ruckert B., et al. Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol 2004; 114: 1425–33
  • Keymeulen B., Vandemeulebroucke E., Ziegler A. G., Mathieu C., Kaufman L., Hale G., et al. Insulin needs after CD3‐antibody therapy in new‐onset type 1 diabetes. N Engl J Med 2005; 352: 2598–608
  • Herold K. C., Gitelman S. E., Masharani U., Hagopian W., Bisikirska B., Donaldson D., et al. A single course of anti‐CD3 monoclonal antibody hOKT3gamma1(Ala‐Ala) results in improvement in C‐peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 2005; 54: 1763–9
  • Belghith M., Bluestone J. A., Barriot S., Megret J., Bach J. F., Chatenoud L. TGF‐beta‐dependent mechanisms mediate restoration of self‐tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 2003; 9: 1202–8
  • Akdis M., Verhagen J., Taylor A., Karamloo F., Karagiannidis C., Crameri R., et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen‐specific T regulatory 1 and T helper 2 cells. J Exp Med 2004; 199: 1567–75
  • Bellinghausen I., Knop J., Saloga J. The role of interleukin 10 in the regulation of allergic immune responses. Int Arch Allergy Immunol 2001; 126: 97–101

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.