International Immunology Advance Access originally published online on October 4, 2004
International Immunology 2004 16(11):1643-1656; doi:10.1093/intimm/dxh165
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 The Japanese Society for Immunology
Featured Article of the Month |
Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells
1 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
2 Department of Gynecology and Obstetrics and 3 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
4 Laboratory of Immunopathology, Research Center for Allergy and Immunology, Institute for Physical and Chemical Research (RIKEN), Yokohama 230-0045, Japan
5 Laboratory of Infection and Prevention, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan
6 Department of Hematology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
7 Core Research for Evolutional Science and Technology (CREST) Program, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan
Correspondence to: S. Sakaguchi; E-mail: shimon{at}frontier.kyoto-u.ac.jp
Naturally occurring CD25+CD4+ regulatory T cells are engaged in the maintenance of immunological self-tolerance and down-regulation of various immune responses. Recent studies with mice showed that Foxp3, which encodes the transcription factor Scurfin, is a master regulatory gene for the development and function of CD25+CD4+ regulatory T cells. Here we examined the role of FOXP3 in human CD25+CD4+ regulatory T cells. The FOXP3 gene and its protein product were preferentially expressed in peripheral CD25+CD4+ T cells, in particular CD25+CD45RO+CD4+ T cells in normal individuals and, interestingly, in some human T cell leukemia virus type 1-infected T cell lines, which constitutively express CD25. TCR stimulation of CD25–CD45RO–CD4+ naive T cells failed to elicit FOXP3 expression at the gene or protein level. Ex vivo retroviral gene transfer of FOXP3, on the other hand, converted peripheral CD25–CD45RO–CD4+ naive T cells into a regulatory T cell phenotype similar to CD25+CD4+ regulatory T cells. For example, FOXP3-transduced T cells exhibited impaired proliferation and production of cytokines including IL-2 and IL-10 upon TCR stimulation, up-regulated the expression of regulatory T cell-associated molecules such as CD25 and CTL-associated antigen-4 and suppressed in vitro proliferation of other T cells in a cell–cell contact-dependent manner. Thus, human FOXP3 is a crucial regulatory gene for the development and function of CD25+CD4+ regulatory T cells, and can be used as their reliable marker. Furthermore, regulatory T cells de novo produced from normal naive T cells by FOXP3 transduction can be instrumental for treatment of autoimmune/inflammatory diseases and negative control of various immune responses.
Keywords: autoimmunity, immune regulation, immunological tolerance, transcription factor
Transmitting editor: T. Hirano
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Zheng, C. N. Manzotti, F. Burke, L. Dussably, O. Qureshi, L. S. K. Walker, and D. M. Sansom Acquisition of Suppressive Function by Activated Human CD4+CD25- T Cells Is Associated with the Expression of CTLA-4 Not FoxP3 J. Immunol., August 1, 2008; 181(3): 1683 - 1691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nagar, H. Vernitsky, Y. Cohen, D. Dominissini, Y. Berkun, G. Rechavi, N. Amariglio, and I. Goldstein Epigenetic inheritance of DNA methylation limits activation-induced expression of FOXP3 in conventional human CD25-CD4+ T cells Int. Immunol., August 1, 2008; 20(8): 1041 - 1055. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Saitoh, N. Yamamoto, M. Z. Dewan, H. Sugimoto, V. J. Martinez Bruyn, Y. Iwasaki, K. Matsubara, X. Qi, T. Saitoh, I. Imoto, et al. Overexpressed NF-{kappa}B-inducing kinase contributes to the tumorigenesis of adult T-cell leukemia and Hodgkin Reed-Sternberg cells Blood, May 15, 2008; 111(10): 5118 - 5129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Ebert, B. S. Tan, J. Browning, S. Svobodova, S. E. Russell, N. Kirkpatrick, C. Gedye, D. Moss, S. P. Ng, D. MacGregor, et al. The Regulatory T Cell-Associated Transcription Factor FoxP3 Is Expressed by Tumor Cells Cancer Res., April 15, 2008; 68(8): 3001 - 3009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Du, C. Huang, B. Zhou, and S. F. Ziegler Isoform-Specific Inhibition of ROR{alpha}-Mediated Transcriptional Activation by Human FOXP3 J. Immunol., April 1, 2008; 180(7): 4785 - 4792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ostad, M. Andersson, A. Gruber, and A. Sundblad Expansion of immunoglobulin autoreactive T-helper cells in multiple myeloma Blood, March 1, 2008; 111(5): 2725 - 2732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yokokawa, V. Cereda, C. Remondo, J. L. Gulley, P. M. Arlen, J. Schlom, and K. Y. Tsang Enhanced Functionality of CD4+CD25highFoxP3+ Regulatory T Cells in the Peripheral Blood of Patients with Prostate Cancer Clin. Cancer Res., February 15, 2008; 14(4): 1032 - 1040. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Atanackovic, N. K. Altorki, Y. Cao, E. Ritter, C. A. Ferrara, G. Ritter, E. W. Hoffman, C. Bokemeyer, L. J. Old, and S. Gnjatic Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming PNAS, February 5, 2008; 105(5): 1650 - 1655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z.-W. Xia, L.-Q. Xu, W.-W. Zhong, J.-J. Wei, N.-L. Li, J. Shao, Y.-Z. Li, S.-C. Yu, and Z.-L. Zhang Heme Oxygenase-1 Attenuates Ovalbumin-Induced Airway Inflammation by Up-Regulation of Foxp3 T-Regulatory Cells, Interleukin-10, and Membrane-Bound Transforming Growth Factor- 1 Am. J. Pathol., December 1, 2007; 171(6): 1904 - 1914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ribot, G. Enault, S. Pilipenko, A. Huchenq, M. Calise, D. Hudrisier, P. Romagnoli, and J. P. M. van Meerwijk Shaping of the Autoreactive Regulatory T Cell Repertoire by Thymic Cortical Positive Selection J. Immunol., November 15, 2007; 179(10): 6741 - 6748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D. Reynolds, R. Banerjee, J. Liu, H. E. Gendelman, and R. L. Mosley Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson's disease J. Leukoc. Biol., November 1, 2007; 82(5): 1083 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Q. Tran, H. Ramsey, and E. M. Shevach Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-{beta} dependent but does not confer a regulatory phenotype Blood, October 15, 2007; 110(8): 2983 - 2990. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Watanabe, P. N. M. Mwinzi, C. L. Black, E. M. O. Muok, D. M. S. Karanja, W. E. Secor, and D. G. Colley T Regulatory Cell Levels Decrease in People Infected With Schistosoma mansoni on Effective Treatment Am J Trop Med Hyg, October 1, 2007; 77(4): 676 - 682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sasaki, H. Ikeda, S. Sawada, Y. Sato, and Y. Nakanuma Naturally-occurring regulatory T cells are increased in inflamed portal tracts with cholangiopathy in primary biliary cirrhosis J. Clin. Pathol., October 1, 2007; 60(10): 1102 - 1107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Oberle, N. Eberhardt, C. S. Falk, P. H. Krammer, and E. Suri-Payer Rapid Suppression of Cytokine Transcription in Human CD4+CD25 T Cells by CD4+Foxp3+ Regulatory T Cells: Independence of IL-2 Consumption, TGF-beta, and Various Inhibitors of TCR Signaling J. Immunol., September 15, 2007; 179(6): 3578 - 3587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. J. de Boer, C. M. van der Loos, P. Teeling, A. C. van der Wal, and M. B.M. Teunissen Immunohistochemical Analysis of Regulatory T Cell Markers FOXP3 and GITR on CD4+CD25+ T Cells in Normal Skin and Inflammatory Dermatoses J. Histochem. Cytochem., September 1, 2007; 55(9): 891 - 898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Kapp, K. Honjo, L. M. Kapp, K. Goldsmith, and R. P. Bucy Antigen, in the Presence of TGF-beta, Induces Up-Regulation of FoxP3gfp+ in CD4+ TCR Transgenic T Cells That Mediate Linked Suppression of CD8+ T Cell Responses J. Immunol., August 15, 2007; 179(4): 2105 - 2114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Cao, E. Dobrzynski, L. Wang, S. Nayak, B. Mingle, C. Terhorst, and R. W. Herzog Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer Blood, August 15, 2007; 110(4): 1132 - 1140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Eastell, BSPAR Study Group, A. Hinks, and W. Thomson SNPs in the FOXP3 gene region show no association with Juvenile Idiopathic Arthritis in a UK Caucasian population Rheumatology, August 1, 2007; 46(8): 1263 - 1265. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Nesburn, I. Bettahi, G. Dasgupta, A. A. Chentoufi, X. Zhang, S. You, N. Morishige, A. J. Wahlert, D. J. Brown, J. V. Jester, et al. Functional Foxp3+ CD4+ CD25(Bright+) "Natural" Regulatory T Cells Are Abundant in Rabbit Conjunctiva and Suppress Virus-Specific CD4+ and CD8+ Effector T Cells during Ocular Herpes Infection J. Virol., July 15, 2007; 81(14): 7647 - 7661. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Yates, F. Rovis, P. Mitchell, B. Afzali, J.-S Tsang, M. Garin, R. Lechler, G. Lombardi, and O. Garden The maintenance of human CD4+CD25+ regulatory T cell function: IL-2, IL-4, IL-7 and IL-15 preserve optimal suppressive potency in vitro Int. Immunol., June 1, 2007; 19(6): 785 - 799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-M Cepika, I. Marinic, J. Morovic-Vergles, D. Soldo-Juresa, and A. Gagro Letter To the Editor: Effect of steroids on the frequency of regulatory T Cells and expression of FOXP3 in a patient with systemic lupus erythematosus: a two-year follow-up Lupus, May 1, 2007; 16(5): 374 - 377. [PDF]
|
|
|
|
|
|
L. E. Pereira, F. Villinger, N. Onlamoon, P. Bryan, A. Cardona, K. Pattanapanysat, K. Mori, S. Hagen, L. Picker, and A. A. Ansari Simian Immunodeficiency Virus (SIV) Infection Influences the Level and Function of Regulatory T Cells in SIV-Infected Rhesus Macaques but Not SIV-Infected Sooty Mangabeys J. Virol., May 1, 2007; 81(9): 4445 - 4456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I L Huibregtse, A U van Lent, and S J H van Deventer Immunopathogenesis of IBD: insufficient suppressor function in the gut? Gut, April 1, 2007; 56(4): 584 - 592. [Full Text] [PDF]
|
|
|
|
|
|
S. E. Allan, S. Q. Crome, N. K. Crellin, L. Passerini, T. S. Steiner, R. Bacchetta, M. G. Roncarolo, and M. K. Levings Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production Int. Immunol., April 1, 2007; 19(4): 345 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. J. Taylor, D. R. Alexander, J. C. Cooper, C. F. Higgins, and J. I. Elliott Regulatory T Cells Are Resistant to Apoptosis via TCR but Not P2X7 J. Immunol., March 15, 2007; 178(6): 3474 - 3482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Zheng, J. Wang, P. Wang, J. D. Gray, and D. A. Horwitz IL-2 Is Essential for TGF-beta to Convert Naive CD4+CD25- Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells J. Immunol., February 15, 2007; 178(4): 2018 - 2027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Daniel, N. Sartory, N. Zahn, G. Geisslinger, H. H. Radeke, and J. M. Stein FTY720 Ameliorates Th1-Mediated Colitis in Mice by Directly Affecting the Functional Activity of CD4+CD25+ Regulatory T Cells J. Immunol., February 15, 2007; 178(4): 2458 - 2468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Kekalainen, H. Tuovinen, J. Joensuu, M. Gylling, R. Franssila, N. Pontynen, K. Talvensaari, J. Perheentupa, A. Miettinen, and T. P. Arstila A Defect of Regulatory T Cells in Patients with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy J. Immunol., January 15, 2007; 178(2): 1208 - 1215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nair, D. Boczkowski, M. Fassnacht, D. Pisetsky, and E. Gilboa Vaccination against the Forkhead Family Transcription Factor Foxp3 Enhances Tumor Immunity Cancer Res., January 1, 2007; 67(1): 371 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bodor, Z. Fehervari, B. Diamond, and S. Sakaguchi Regulatory T cell-mediated suppression: potential role of ICER J. Leukoc. Biol., January 1, 2007; 81(1): 161 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Hoffmann, R. Eder, T. J. Boeld, K. Doser, B. Piseshka, R. Andreesen, and M. Edinger Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion Blood, December 15, 2006; 108(13): 4260 - 4267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Tuovinen, J. T. Salminen, and T. P. Arstila Most human thymic and peripheral-blood CD4+CD25+ regulatory T cells express 2 T-cell receptors Blood, December 15, 2006; 108(13): 4063 - 4070. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Tiittanen, J. T. Huupponen, M. Knip, and O. Vaarala Insulin Treatment in Patients With Type 1 Diabetes Induces Upregulation of Regulatory T-Cell Markers in Peripheral Blood Mononuclear Cells Stimulated With Insulin In Vitro Diabetes, December 1, 2006; 55(12): 3446 - 3454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-B. Sun, S. Raghavan, A. Sjoling, S. Lundin, and J. Holmgren Oral Tolerance Induction with Antigen Conjugated to Cholera Toxin B Subunit Generates Both Foxp3+CD25+ and Foxp3-CD25- CD4+ Regulatory T Cells J. Immunol., December 1, 2006; 177(11): 7634 - 7644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tellier, J. P. M. van Meerwijk, and P. Romagnoli An MHC-linked locus modulates thymic differentiation of CD4+CD25+Foxp3+ regulatory T lymphocytes Int. Immunol., November 1, 2006; 18(11): 1509 - 1519. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Kapp, K. Honjo, L. M. Kapp, X. y. Xu, A. Cozier, and R. P. Bucy TCR transgenic CD8+ T cells activated in the presence of TGF{beta} express FoxP3 and mediate linked suppression of primary immune responses and cardiac allograft rejection Int. Immunol., November 1, 2006; 18(11): 1549 - 1562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Lawson, A. K. Brown, V. Bejarano, S. H. Douglas, C. H. Burgoyne, A. S. Greenstein, A. W. Boylston, P. Emery, F. Ponchel, and J. D. Isaacs Early rheumatoid arthritis is associated with a deficit in the CD4+CD25high regulatory T cell population in peripheral blood Rheumatology, October 1, 2006; 45(10): 1210 - 1217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Toda and C. A. Piccirillo Development and function of naturally occurring CD4+CD25+ regulatory T cells J. Leukoc. Biol., September 1, 2006; 80(3): 458 - 470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Lopes, T. R. Torgerson, L. A. Schubert, S. D. Anover, E. L. Ocheltree, H. D. Ochs, and S. F. Ziegler Analysis of FOXP3 Reveals Multiple Domains Required for Its Function as a Transcriptional Repressor. J. Immunol., September 1, 2006; 177(5): 3133 - 3142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Rezvani, S. Mielke, M. Ahmadzadeh, Y. Kilical, B. N. Savani, J. Zeilah, K. Keyvanfar, A. Montero, N. Hensel, R. Kurlander, et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT Blood, August 15, 2006; 108(4): 1291 - 1297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. W. Lim, H. E. Broxmeyer, and C. H. Kim Regulation of Trafficking Receptor Expression in Human Forkhead Box P3+ Regulatory T Cells J. Immunol., July 15, 2006; 177(2): 840 - 851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Wing, Z. Fehervari, and S. Sakaguchi Emerging possibilities in the development and function of regulatory T cells Int. Immunol., July 1, 2006; 18(7): 991 - 1000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Valencia, G. Stephens, R. Goldbach-Mansky, M. Wilson, E. M. Shevach, and P. E. Lipsky TNF downmodulates the function of human CD4+CD25hi T-regulatory cells Blood, July 1, 2006; 108(1): 253 - 261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Condomines, P. Quittet, Z.-Y. Lu, L. Nadal, P. Latry, E. Lopez, M. Baudard, G. Requirand, C. Duperray, J.-F. Schved, et al. Functional Regulatory T Cells Are Collected in Stem Cell Autografts by Mobilization with High-Dose Cyclophosphamide and Granulocyte Colony-Stimulating Factor. J. Immunol., June 1, 2006; 176(11): 6631 - 6639. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Benigni, S. Tomasoni, L. A. Turka, L. Longaretti, L. Zentilin, M. Mister, A. Pezzotta, N. Azzollini, M. Noris, S. Conti, et al. Adeno-Associated Virus-Mediated CTLA4Ig Gene Transfer Protects MHC-Mismatched Renal Allografts from Chronic Rejection J. Am. Soc. Nephrol., June 1, 2006; 17(6): 1665 - 1672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Liu, M. Komai-Koma, D. Xu, and F. Y. Liew Toll-like receptor 2 signaling modulates the functions of CD4+CD25+ regulatory T cells PNAS, May 2, 2006; 103(18): 7048 - 7053. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Gavin, T. R. Torgerson, E. Houston, P. deRoos, W. Y. Ho, A. Stray-Pedersen, E. L. Ocheltree, P. D. Greenberg, H. D. Ochs, and A. Y. Rudensky Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development PNAS, April 25, 2006; 103(17): 6659 - 6664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Baecher-Allan, E. Wolf, and D. A. Hafler MHC class II expression identifies functionally distinct human regulatory T cells. J. Immunol., April 15, 2006; 176(8): 4622 - 4631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ono, J. Shimizu, Y. Miyachi, and S. Sakaguchi Control of Autoimmune Myocarditis and Multiorgan Inflammation by Glucocorticoid-Induced TNF Receptor Family-Related Proteinhigh, Foxp3-Expressing CD25+ and CD25- Regulatory T Cells. J. Immunol., April 15, 2006; 176(8): 4748 - 4756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Jee, R. Liu, X.-F. Bai, D. I. Campagnolo, F.-D. Shi, and T. L. Vollmer Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis? Int. Immunol., April 1, 2006; 18(4): 537 - 544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. Fecci, D. A. Mitchell, J. F. Whitesides, W. Xie, A. H. Friedman, G. E. Archer, J. E. Herndon II, D. D. Bigner, G. Dranoff, and J. H. Sampson Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res., March 15, 2006; 66(6): 3294 - 3302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Zheng, J. H. Wang, W. Stohl, K. S. Kim, J. D. Gray, and D. A. Horwitz TGF-beta Requires CTLA-4 Early after T Cell Activation to Induce FoxP3 and Generate Adaptive CD4+CD25+ Regulatory Cells J. Immunol., March 15, 2006; 176(6): 3321 - 3329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ahmadzadeh and S. A. Rosenberg IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients Blood, March 15, 2006; 107(6): 2409 - 2414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Rieger, C. Loddenkemper, J. Maul, T. Fietz, |