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Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
CD4+CD25+ T cells represent a unique population of "professional" suppressor T cells that prevent induction of organ-specific autoimmune disease. In vitro, CD4+CD25+ cells were anergic to simulation via the TCR and when cultured with CD4+CD25- cells, markedly suppressed polyclonal T cell proliferation by specifically inhibiting the production of IL-2. Suppression was cytokine independent, cell contact dependent, and required activation of the suppressors via their TCR. Further characterization of the CD4+CD25+ population demonstrated that they do not contain memory or activated T cells and that they act through an APC-independent mechanism. CD4+CD25+ T cells isolated from TCR transgenic (Tg) mice inhibited responses of CD4+CD25- Tg T cells to the same Ag, but also inhibited the Ag-specific responses of Tg cells specific for a distinct Ag. Suppression required that both peptide/MHC complexes be present in the same culture, but the Ags could be presented by two distinct populations of APC. When CD4+CD25+ T cells were cultured with anti-CD3 and IL-2, they expanded, remained anergic, and in the absence of restimulation via their TCR, suppressed Ag-specific responses of CD4+CD25- T cells from multiple TCR transgenics. Collectively, these data demonstrate that CD4+CD25+ T cells require activation via their TCR to become suppressive, but once activated, their suppressor effector function is completely nonspecific. The cell surface molecules involved in this T-T interaction remain to be characterized.
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 C. T. Viehl, T. T. Moore, U. K. Liyanage, D. M. Frey, J. P. Ehlers, T. J. Eberlein, P. S. Goedegebuure, and D. C. Linehan Depletion of CD4+CD25+ Regulatory T Cells Promotes a Tumor-Specific Immune Response in Pancreas Cancer-Bearing Mice Ann. Surg. Oncol., September 1, 2006; 13(9): 1252 - 1258. [Abstract] [Full Text] [PDF]
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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]
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F. Billiard, E. Litvinova, D. Saadoun, F. Djelti, D. Klatzmann, J. L. Cohen, G. Marodon, and B. L. Salomon Regulatory and Effector T Cell Activation Levels Are Prime Determinants of In Vivo Immune Regulation J. Immunol., August 15, 2006; 177(4): 2167 - 2174. [Abstract] [Full Text] [PDF]
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S. Wei, I. Kryczek, and W. Zou Regulatory T-cell compartmentalization and trafficking Blood, July 15, 2006; 108(2): 426 - 431. [Abstract] [Full Text] [PDF]
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J. Y.-S. Tsang, N. O. S. Camara, E. Eren, H. Schneider, C. Rudd, G. Lombardi, and R. Lechler Altered proximal T cell receptor (TCR) signaling in human CD4+CD25+ regulatory T cells J. Leukoc. Biol., July 1, 2006; 80(1): 145 - 151. [Abstract] [Full Text] [PDF]
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M. Mahic, S. Yaqub, C. C. Johansson, K. Tasken, and E. M. Aandahl FOXP3+CD4+CD25+ Adaptive Regulatory T Cells Express Cyclooxygenase-2 and Suppress Effector T Cells by a Prostaglandin E2-Dependent Mechanism J. Immunol., July 1, 2006; 177(1): 246 - 254. [Abstract] [Full Text] [PDF]
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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]
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H.-Y. Qin, R. Mukherjee, E. Lee-Chan, C. Ewen, R. C. Bleackley, and B. Singh A novel mechanism of regulatory T cell-mediated down-regulation of autoimmunity Int. Immunol., July 1, 2006; 18(7): 1001 - 1015. [Abstract] [Full Text] [PDF]
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H. Inaba and T. L. Geiger Defective cell cycle induction by IL-2 in naive T-cells antigen stimulated in the presence of refractory T-lymphocytes Int. Immunol., July 1, 2006; 18(7): 1043 - 1054. [Abstract] [Full Text] [PDF]
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A. Noble, A. Giorgini, and J. A. Leggat Cytokine-induced IL-10-secreting CD8 T cells represent a phenotypically distinct suppressor T-cell lineage Blood, June 1, 2006; 107(11): 4475 - 4483. [Abstract] [Full Text] [PDF]
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T. L. Vanasek, S. L. Nandiwada, M. K. Jenkins, and D. L. Mueller CD25+Foxp3+ Regulatory T Cells Facilitate CD4+ T Cell Clonal Anergy Induction during the Recovery from Lymphopenia J. Immunol., May 15, 2006; 176(10): 5880 - 5889. [Abstract] [Full Text] [PDF]
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H. Nishikawa, F. Qian, T. Tsuji, G. Ritter, L. J. Old, S. Gnjatic, and K. Odunsi Influence of CD4+CD25+ Regulatory T Cells on Low/High-Avidity CD4+ T Cells following Peptide Vaccination J. Immunol., May 15, 2006; 176(10): 6340 - 6346. [Abstract] [Full Text] [PDF]
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M. Beyer, M. Kochanek, T. Giese, E. Endl, M. R. Weihrauch, P. A. Knolle, S. Classen, and J. L. Schultze In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma Blood, May 15, 2006; 107(10): 3940 - 3949. [Abstract] [Full Text] [PDF]
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D.-M. Zhao, A. M. Thornton, R. J. DiPaolo, and E. M. Shevach Activated CD4+CD25+ T cells selectively kill B lymphocytes Blood, May 15, 2006; 107(10): 3925 - 3932. [Abstract] [Full Text] [PDF]
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M. Gad, D. Lundsgaard, S. Kjellev, N. N Kristensen, T. Seremet, P. t. Straten, and M. H Claesson Reactivity of naive CD4+CD25- T cells against gut microflora in healthy mice Int. Immunol., May 1, 2006; 18(5): 817 - 825. [Abstract] [Full Text] [PDF]
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J. J. A. Coenen, H. J. P. M. Koenen, E. van Rijssen, L. Boon, I. Joosten, and L. B. Hilbrands CTLA-4 Engagement and Regulatory CD4+CD25+ T Cells Independently Control CD8+-Mediated Responses under Costimulation Blockade J. Immunol., May 1, 2006; 176(9): 5240 - 5246. [Abstract] [Full Text] [PDF]
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R. Houot, I. Perrot, E. Garcia, I. Durand, and S. Lebecque Human CD4+CD25high Regulatory T Cells Modulate Myeloid but Not Plasmacytoid Dendritic Cells Activation J. Immunol., May 1, 2006; 176(9): 5293 - 5298. [Abstract] [Full Text] [PDF]
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K. S. Nicolson, E. J. O'Neill, A. Sundstedt, H. B. Streeter, S. Minaee, and D. C. Wraith Antigen-Induced IL-10+ Regulatory T Cells Are Independent of CD25+ Regulatory Cells for Their Growth, Differentiation, and Function J. Immunol., May 1, 2006; 176(9): 5329 - 5337. [Abstract] [Full Text] [PDF]
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T. Kanai, K. Tanimoto, Y. Nemoto, R. Fujii, S. Makita, T. Totsuka, and M. Watanabe Naturally arising CD4+CD25+ regulatory T cells suppress the expansion of colitogenic CD4+CD44highCD62L- effector memory T cells Am J Physiol Gastrointest Liver Physiol, May 1, 2006; 290(5): G1051 - G1058. [Abstract] [Full Text] [PDF]
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C. E. Tadokoro, G. Shakhar, S. Shen, Y. Ding, A. C. Lino, A. Maraver, J. J. Lafaille, and M. L. Dustin Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo J. Exp. Med., March 20, 2006; 203(3): 505 - 511. [Abstract] [Full Text] [PDF]
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P.-Y. Mantel, N. Ouaked, B. Ruckert, C. Karagiannidis, R. Welz, K. Blaser, and C. B. Schmidt-Weber Molecular Mechanisms Underlying FOXP3 Induction in Human T Cells J. Immunol., March 15, 2006; 176(6): 3593 - 3602. [Abstract] [Full Text] [PDF]
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H. Keino, M. Takeuchi, T. Kezuka, T. Hattori, M. Usui, O. Taguchi, J. W. Streilein, and J. Stein-Streilein Induction of Eye-Derived Tolerance Does Not Depend on Naturally Occurring CD4+CD25+ T Regulatory Cells. Invest. Ophthalmol. Vis. Sci., March 1, 2006; 47(3): 1047 - 1055. [Abstract] [Full Text] [PDF]
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M. J. Smyth, M. W. L. Teng, J. Swann, K. Kyparissoudis, D. I. Godfrey, and Y. Hayakawa CD4+CD25+ T Regulatory Cells Suppress NK Cell-Mediated Immunotherapy of Cancer J. Immunol., February 1, 2006; 176(3): 1582 - 1587. [Abstract] [Full Text] [PDF]
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T. D. Zwar, S. Read, I. R. van Driel, and P. A. Gleeson CD4+CD25+ Regulatory T Cells Inhibit the Antigen-Dependent Expansion of Self-Reactive T Cells In Vivo J. Immunol., February 1, 2006; 176(3): 1609 - 1617. [Abstract] [Full Text] [PDF]
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A. Trenado, M. Sudres, Q. Tang, S. Maury, F. Charlotte, S. Gregoire, M. Bonyhadi, D. Klatzmann, B. L. Salomon, and J. L. Cohen Ex Vivo-Expanded CD4+CD25+ Immunoregulatory T Cells Prevent Graft-versus-Host-Disease by Inhibiting Activation/Differentiation of Pathogenic T Cells J. Immunol., January 15, 2006; 176(2): 1266 - 1273. [Abstract] [Full Text] [PDF]
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