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1 Plays an Important Role in the Mechanism of CD4+CD25+ Regulatory T Cell Activity in Both Humans and Mice
* Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
In previous studies, we have shown that murine CD4+CD25+ regulatory T cells produce high levels of TGF-
1 in a cell surface and/or secreted form, and blockade of such TGF-1 by anti-TGF- curtails the ability of these cells to suppress CD25- T cell proliferation and B cell Ig production in in vitro suppressor assays. In further support for the role of TGF-1 in suppression by CD4+CD25+ T cells, we show in this study that another TGF-1-blocking molecule, recombinant latency-associated peptide of TGF-1 (rLAP), also reverses suppression by mouse CD4+CD25+ T cells as well as their human counterparts, CD4+CD25high T cells. In addition, we show that CD25- T cells exposed to CD4+CD25+ T cells in vitro manifest activation of Smad-2 and induction of CD103, the latter a TGF--inducible surface integrin. In further studies, we show that while CD4+CD25+ T cells from TGF-1-deficient mice can suppress CD25- T cell proliferation in vitro, these cells do not protect recipient mice from colitis in the SCID transfer model in vivo, and, in addition, CD4+LAP+, but not CD4+LAP- T cells from normal mice protect recipient mice from colitis in this model. Together, these studies demonstrate that TGF-1 produced by CD4+CD25+ T cells is involved in the suppressor activity of these cells, particularly in their ability to regulate intestinal inflammation.
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M. S. Longhi, M. J. Hussain, R. R. Mitry, S. K. Arora, G. Mieli-Vergani, D. Vergani, and Y. Ma Functional Study of CD4+CD25+ Regulatory T Cells in Health and Autoimmune Hepatitis J. Immunol., April 1, 2006; 176(7): 4484 - 4491. [Abstract] [Full Text] [PDF]
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C. Chen, W.-h. Lee, L. Zhong, and C.-P. Liu Regulatory T Cells Can Mediate Their Function through the Stimulation of APCs to Produce Immunosuppressive Nitric Oxide J. Immunol., March 15, 2006; 176(6): 3449 - 3460. [Abstract] [Full Text] [PDF]
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S. Suvas, A. K. Azkur, and B. T. Rouse Qa-1b and CD94-NKG2a Interaction Regulate Cytolytic Activity of Herpes Simplex Virus-Specific Memory CD8+ T Cells in the Latently Infected Trigeminal Ganglia J. Immunol., February 1, 2006; 176(3): 1703 - 1711. [Abstract] [Full Text] [PDF]
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M.-A. Alyanakian, F. Grela, A. Aumeunier, C. Chiavaroli, C. Gouarin, E. Bardel, G. Normier, L. Chatenoud, N. Thieblemont, and J.-F. Bach Transforming Growth Factor-{beta} and Natural Killer T-Cells Are Involved in the Protective Effect of a Bacterial Extract on Type 1 Diabetes Diabetes, January 1, 2006; 55(1): 179 - 185. [Abstract] [Full Text] [PDF]
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U. C. Rogner, F. Lepault, M.-C. Gagnerault, D. Vallois, J. Morin, P. Avner, and C. Boitard The Diabetes Type 1 Locus Idd6 Modulates Activity of CD4+CD25+ Regulatory T-Cells Diabetes, January 1, 2006; 55(1): 186 - 192. [Abstract] [Full Text] [PDF]
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S. Sugita, T. F. Ng, P. J. Lucas, R. E. Gress, and J. W. Streilein B7+ Iris Pigment Epithelium Induce CD8+ T Regulatory Cells; Both Suppress CTLA-4+ T Cells J. Immunol., January 1, 2006; 176(1): 118 - 127. [Abstract] [Full Text] [PDF]
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N. N. Choileain, M. MacConmara, Y. Zang, T. J. Murphy, J. A. Mannick, and J. A. Lederer Enhanced Regulatory T Cell Activity Is an Element of the Host Response to Injury J. Immunol., January 1, 2006; 176(1): 225 - 236. [Abstract] [Full Text] [PDF]
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I. P. Lewkowich, N. S. Herman, K. W. Schleifer, M. P. Dance, B. L. Chen, K. M. Dienger, A. A. Sproles, J. S. Shah, J. Kohl, Y. Belkaid, et al. CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function J. Exp. Med., December 5, 2005; 202(11): 1549 - 1561. [Abstract] [Full Text] [PDF]
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M. L. Fields, B. D. Hondowicz, M. H. Metzgar, S. A. Nish, G. N. Wharton, C. C. Picca, A. J. Caton, and J. Erikson CD4+CD25+ Regulatory T Cells Inhibit the Maturation but Not the Initiation of an Autoantibody Response J. Immunol., October 1, 2005; 175(7): 4255 - 4264. [Abstract] [Full Text] [PDF]
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X. Huang, J. Zhu, and Y. Yang Protection against Autoimmunity in Nonlymphopenic Hosts by CD4+CD25+ Regulatory T Cells Is Antigen-Specific and Requires IL-10 and TGF-{beta} J. Immunol., October 1, 2005; 175(7): 4283 - 4291. [Abstract] [Full Text] [PDF]
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 S. P Cobbold T cell tolerance induced by therapeutic antibodies Phil Trans R Soc B, September 29, 2005; 360(1461): 1695 - 1705. [Abstract] [Full Text] [PDF]
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T. Banovic, K. P. A. MacDonald, E. S. Morris, V. Rowe, R. Kuns, A. Don, J. Kelly, S. Ledbetter, A. D. Clouston, and G. R. Hill TGF-{beta} in allogeneic stem cell transplantation: friend or foe? Blood, September 15, 2005; 106(6): 2206 - 2214. [Abstract] [Full Text] [PDF]
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H. H. Birdsall, W. J. Porter, J. Trial, and R. D. Rossen Monocytes Stimulated by 110-kDa Fibronectin Fragments Suppress Proliferation of Anti-CD3-Activated T Cells J. Immunol., September 1, 2005; 175(5): 3347 - 3353. [Abstract] [Full Text] [PDF]
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 A. Asgharpour, C. Gilchrist, D. Baba, S. Hamano, and E. Houpt Resistance to Intestinal Entamoeba histolytica Infection Is Conferred by Innate Immunity and Gr-1+ Cells Infect. Immun., August 1, 2005; 73(8): 4522 - 4529. [Abstract] [Full Text] [PDF]
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V. Gillan and E. Devaney Regulatory T Cells Modulate Th2 Responses Induced by Brugia pahangi Third-Stage Larvae Infect. Immun., July 1, 2005; 73(7): 4034 - 4042. [Abstract] [Full Text] [PDF]
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 L. Liu, Z. Xu, R. C. Fuhlbrigge, V. Pena-Cruz, J. Lieberman, and T. S. Kupper Vaccinia Virus Induces Strong Immunoregulatory Cytokine Production in Healthy Human Epidermal Keratinocytes: a Novel Strategy for Immune Evasion J. Virol., June 15, 2005; 79(12): 7363 - 7370. [Abstract] [Full Text] [PDF]
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S. Sharma, S.-C. Yang, L. Zhu, K. Reckamp, B. Gardner, F. Baratelli, M. Huang, R. K. Batra, and S. M. Dubinett Tumor Cyclooxygenase-2/Prostaglandin E2-Dependent Promotion of FOXP3 Expression and CD4+CD25+ T Regulatory Cell Activities in Lung Cancer Cancer Res., June 15, 2005; 65(12): 5211 - 5220. [Abstract] [Full Text] [PDF]
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T. L. Denning, G. Kim, and M. Kronenberg Cutting Edge: CD4+CD25+ Regulatory T Cells Impaired for Intestinal Homing Can Prevent Colitis J. Immunol., June 15, 2005; 174(12): 7487 - 7491. [Abstract] [Full Text] [PDF]
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L. Myers, M. Croft, B. S. Kwon, R. S. Mittler, and A. T. Vella Peptide-Specific CD8 T Regulatory Cells Use IFN-{gamma} to Elaborate TGF-{beta}-Based Suppression J. Immunol., June 15, 2005; 174(12): 7625 - 7632. [Abstract] [Full Text] [PDF]
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T. M. Brusko, C. H. Wasserfall, M. J. Clare-Salzler, D. A. Schatz, and M. A. Atkinson Functional Defects and the Influence of Age on the Frequency of CD4+CD25+ T-Cells in Type 1 Diabetes Diabetes, May 1, 2005; 54(5): 1407 - 1414. [Abstract] [Full Text] [PDF]
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T. M. Brusko, C. H. Wasserfall, A. Agarwal, M. H. Kapturczak, and M. A. Atkinson An Integral Role for Heme Oxygenase-1 and Carbon Monoxide in Maintaining Peripheral Tolerance by CD4+CD25+ Regulatory T Cells J. Immunol., May 1, 2005; 174(9): 5181 - 5186. [Abstract] [Full Text] [PDF]
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S. M. Pop, C. P. Wong, D. A. Culton, S. H. Clarke, and R. Tisch Single cell analysis shows decreasing FoxP3 and TGF{beta}1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes J. Exp. Med., April 18, 2005; 201(8): 1333 - 1346. [Abstract] [Full Text] [PDF]
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I. Lee, L. Wang, A. D. Wells, M. E. Dorf, E. Ozkaynak, and W. W. Hancock Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor J. Exp. Med., April 4, 2005; 201(7): 1037 - 1044. [Abstract] [Full Text] [PDF]
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D. W. Smith and C. Nagler-Anderson Preventing Intolerance: The Induction of Nonresponsiveness to Dietary and Microbial Antigens in the Intestinal Mucosa J. Immunol., April 1, 2005; 174(7): 3851 - 3857. [Abstract] [Full Text] [PDF]
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M. Kleinewietfeld, F. Puentes, G. Borsellino, L. Battistini, O. Rotzschke, and K. Falk CCR6 expression defines regulatory effector/memory-like cells within the CD25+CD4+ T-cell subset Blood, April 1, 2005; 105(7): 2877 - 2886. [Abstract] [Full Text] [PDF]
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C. Di Giacinto, M. Marinaro, M. Sanchez, W. Strober, and M. Boirivant Probiotics Ameliorate Recurrent Th1-Mediated Murine Colitis by Inducing IL-10 and IL-10-Dependent TGF-{beta}-Bearing Regulatory Cells J. Immunol., March 15, 2005; 174(6): 3237 - 3246. [Abstract] [Full Text] [PDF]
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H.-K. Kang, M. A. Michaels, B. R. Berner, and S. K. Datta Very Low-Dose Tolerance with Nucleosomal Peptides Controls Lupus and Induces Potent Regulatory T Cell Subsets J. Immunol., March 15, 2005; 174(6): 3247 - 3255. [Abstract] [Full Text] [PDF]
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D. C. Gondek, L.-F. Lu, S. A. Quezada, S. Sakaguchi, and R. J. Noelle Cutting Edge: Contact-Mediated Suppression by CD4+CD25+ Regulatory Cells Involves a Granzyme B-Dependent, Perforin-Independent Mechanism J. Immunol., February 15, 2005; 174(4): 1783 - 1786. [Abstract] [Full Text] [PDF]
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C Veltkamp, R B Sartor, T Giese, F Autschbach, I Kaden, R Veltkamp, D Rost, B Kallinowski, and W Stremmel Regulatory CD4+CD25+ cells reverse imbalances in the T cell pool of bone marrow transplanted TG{varepsilon}26 mice leading to the prevention of colitis Gut, February 1, 2005; 54(2): 207 - 214. [Abstract] [Full Text] [PDF]
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P. E. Rao, A. L. Petrone, and P. D. Ponath Differentiation and Expansion of T Cells with Regulatory Function from Human Peripheral Lymphocytes by Stimulation in the Presence of TGF-{beta} J. Immunol., February 1, 2005; 174(3): 1446 - 1455. [Abstract] [Full Text] [PDF]
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W. R. Godfrey, D. J. Spoden, Y. G. Ge, S. R. Baker, B. Liu, B. L. Levine, C. H. June, B. R. Blazar, and S. B. Porter Cord blood CD4+CD25+-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function Blood, January 15, 2005; 105(2): 750 - 758. [Abstract] [Full Text] [PDF]
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