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The Journal of Immunology, 2004, 172: 5149-5153.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: TGF-{beta} Induces a Regulatory Phenotype in CD4+CD25– T Cells through Foxp3 Induction and Down-Regulation of Smad7

Massimo C. Fantini*, Christoph Becker*, Giovanni Monteleone{dagger}, Francesco Pallone{dagger}, Peter R. Galle* and Markus F. Neurath1,*

* Laboratory of Immunology, I. Medical Clinic, Johannes Gutenberg University of Mainz, Mainz, Germany; and {dagger} Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy

CD4+CD25+ regulatory cells are a subpopulation of T lymphocytes of thymic origin. However, recent data suggest an alternative commitment of regulatory T cells in the periphery, although the precise mechanism is unknown. In the present work, we demonstrate that TGF-{beta} is able to induce Foxp3 expression and subsequently a regulatory phenotype in CD4+CD25– peripheral murine T cells. Similarly, TGF-{beta} induced Foxp3 in human CD4+CD25– T cells. Moreover, we show that the inhibitory Smad7 protein that is normally induced by TGF-{beta} and limits TGF-{beta} signaling, is strongly down-regulated by Foxp3 at the transcriptional level. Foxp3-mediated down-regulation of Smad7 subsequently rendered CD4+CD25– T cells highly susceptible to the morphogenic and regulatory effects of TGF-{beta} signaling via Smad3/4. In summary, we demonstrate that TGF-{beta} induces a regulatory phenotype in CD4+CD25– T cells through the induction of Foxp3 and a positive autoregulatory loop of TGF-{beta} signaling due to the absence of Smad7.




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J. Exp. Med., August 6, 2007; 204(8): 1775 - 1785.
[Abstract] [Full Text] [PDF]

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 JEMHome page
M. J. Benson, K. Pino-Lagos, M. Rosemblatt, and R. J. Noelle
All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation
J. Exp. Med., August 6, 2007; 204(8): 1765 - 1774.
[Abstract] [Full Text] [PDF]

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 J. Leukoc. Biol.Home page
M. Pyzik and C. A. Piccirillo
TGF-{beta}1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets
J. Leukoc. Biol., August 1, 2007; 82(2): 335 - 346.
[Abstract] [Full Text] [PDF]

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 J. Leukoc. Biol.Home page
S.-J. Liu, J.-P. Tsai, C.-R. Shen, Y.-P. Sher, C.-L. Hsieh, Y.-C. Yeh, A.-H. Chou, S.-R. Chang, K.-N. Hsiao, F.-W. Yu, et al.
Induction of a distinct CD8 Tnc17 subset by transforming growth factor-{beta} and interleukin-6
J. Leukoc. Biol., August 1, 2007; 82(2): 354 - 360.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
T. So and M. Croft
Cutting Edge: OX40 Inhibits TGF-beta- and Antigen-Driven Conversion of Naive CD4 T Cells into CD25+Foxp3+ T cells
J. Immunol., August 1, 2007; 179(3): 1427 - 1430.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
K. Nakagome, M. Dohi, K. Okunishi, R. Tanaka, T. Kouro, M. R. Kano, K. Miyazono, J.-i. Miyazaki, K. Takatsu, and K. Yamamoto
IL-5-Induced Hypereosinophilia Suppresses the Antigen-Induced Immune Response via a TGF-beta-Dependent Mechanism
J. Immunol., July 1, 2007; 179(1): 284 - 294.
[Abstract] [Full Text] [PDF]

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 JCOHome page
G. Cesana and H. L. Kaufman
In Reply
J. Clin. Oncol., June 20, 2007; 25(18): 2630 - 2632.
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 J. Immunol.Home page
R. K. Selvaraj and T. L. Geiger
A Kinetic and Dynamic Analysis of Foxp3 Induced in T Cells by TGF-beta
J. Immunol., June 15, 2007; 178(12): 7667 - 7677.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
J. Wong, R. Obst, M. Correia-Neves, G. Losyev, D. Mathis, and C. Benoist
Adaptation of TCR Repertoires to Self-Peptides in Regulatory and Nonregulatory CD4+ T Cells
J. Immunol., June 1, 2007; 178(11): 7032 - 7041.
[Abstract] [Full Text] [PDF]

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 BloodHome page
Z. Yao, Y. Kanno, M. Kerenyi, G. Stephens, L. Durant, W. T. Watford, A. Laurence, G. W. Robinson, E. M. Shevach, R. Moriggl, et al.
Nonredundant roles for Stat5a/b in directly regulating Foxp3
Blood, May 15, 2007; 109(10): 4368 - 4375.
[Abstract] [Full Text] [PDF]

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 J. Virol.Home page
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]

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 Infect. Immun.Home page
I. Peluso, D. Fina, R. Caruso, C. Stolfi, F. Caprioli, M. C. Fantini, G. Caspani, E. Grossi, L. Di Iorio, F. M. Paone, et al.
Lactobacillus paracasei subsp. paracasei B21060 Suppresses Human T-Cell Proliferation
Infect. Immun., April 1, 2007; 75(4): 1730 - 1737.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
T. S. Davidson, R. J. DiPaolo, J. Andersson, and E. M. Shevach
Cutting Edge: IL-2 Is Essential for TGF-beta-Mediated Induction of Foxp3+ T Regulatory Cells
J. Immunol., April 1, 2007; 178(7): 4022 - 4026.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
K. N. Couper, D. G. Blount, J. B. de Souza, I. Suffia, Y. Belkaid, and E. M. Riley
Incomplete Depletion and Rapid Regeneration of Foxp3+ Regulatory T Cells Following Anti-CD25 Treatment in Malaria-Infected Mice
J. Immunol., April 1, 2007; 178(7): 4136 - 4146.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
D. Haribhai, W. Lin, L. M. Relland, N. Truong, C. B. Williams, and T. A. Chatila
Regulatory T Cells Dynamically Control the Primary Immune Response to Foreign Antigen
J. Immunol., March 1, 2007; 178(5): 2961 - 2972.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
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]

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 Int ImmunolHome page
G. Yang, A. Liu, Q. Xie, T. B. Guo, B. Wan, B. Zhou, and J. Z. Zhang
Association of CD4+CD25+Foxp3+ regulatory T cells with chronic activity and viral clearance in patients with hepatitis B
Int. Immunol., February 1, 2007; 19(2): 133 - 140.
[Abstract] [Full Text] [PDF]

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 JEMHome page
S. Nadkarni, C. Mauri, and M. R. Ehrenstein
Anti-TNF-{alpha} therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-{beta}
J. Exp. Med., January 22, 2007; 204(1): 33 - 39.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
I. Peluso, M. C. Fantini, D. Fina, R. Caruso, M. Boirivant, T. T. MacDonald, F. Pallone, and G. Monteleone
IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes
J. Immunol., January 15, 2007; 178(2): 732 - 739.
[Abstract] [Full Text] [PDF]

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 J. Leukoc. Biol.Home page
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]

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 J. Immunol.Home page
P. Bochtler, C. Wahl, R. Schirmbeck, and J. Reimann
Functional Adaptive CD4 Foxp3 T Cells Develop in MHC Class II-Deficient Mice
J. Immunol., December 15, 2006; 177(12): 8307 - 8314.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
C. A. Learn, P. E. Fecci, R. J. Schmittling, W. Xie, I. Karikari, D. A. Mitchell, G. E. Archer, Z. Wei, H. Dressman, and J. H. Sampson
Profiling of CD4+, CD8+, and CD4+CD25+CD45RO+FoxP3+ T Cells in Patients with Malignant Glioma Reveals Differential Expression of the Immunologic Transcriptome Compared with T Cells from Healthy Volunteers
Clin. Cancer Res., December 15, 2006; 12(24): 7306 - 7315.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
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]

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J. Nilsson, A. Boasso, P. A. Velilla, R. Zhang, M. Vaccari, G. Franchini, G. M. Shearer, J. Andersson, and C. Chougnet
HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS
Blood, December 1, 2006; 108(12): 3808 - 3817.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
T. L. Sukiennicki and D. J. Fowell
Distinct Molecular Program Imposed on CD4+ T Cell Targets by CD4+CD25+ Regulatory T Cells
J. Immunol., November 15, 2006; 177(10): 6952 - 6961.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
H. H. Uhlig, J. Coombes, C. Mottet, A. Izcue, C. Thompson, A. Fanger, A. Tannapfel, J. D. Fontenot, F. Ramsdell, and F. Powrie
Characterization of Foxp3+CD4+CD25+ and IL-10-Secreting CD4+CD25+ T Cells during Cure of Colitis
J. Immunol., November 1, 2006; 177(9): 5852 - 5860.
[Abstract] [Full Text] [PDF]

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 J. Immunol.Home page
Z.-W. Xia, W.-W. Zhong, L.-Q. Xu, J.-L. Sun, Q.-X. Shen, J.-G. Wang, J. Shao, Y.-Z. Li, and S.-C. Yu
Heme Oxygenase-1-Mediated CD4+CD25high Regulatory T Cells Suppress Allergic Airway Inflammation
J. Immunol., November 1, 2006; 177(9): 5936 - 5945.
[Abstract] [Full Text] [PDF]

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 Int ImmunolHome page
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]

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S. Hue, P. Ahern, S. Buonocore, M. C. Kullberg, D. J. Cua, B. S. McKenzie, F. Powrie, and K. J. Maloy
Interleukin-23 drives innate and T cell-mediated intestinal inflammation
J. Exp. Med., October 30, 2006; 203(11): 2473 - 2483.
[Abstract] [Full Text] [PDF]


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