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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. Fozza, E. Nadal, M. Longinotti, and F. Dazzi T-cell receptor repertoire usage after allografting differs between CD4+CD25+ regulatory T cells and their CD4+CD25 counterpart Haematologica, February 1, 2007; 92(2): 206 - 214. [Abstract] [Full Text] [PDF]
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D. Golshayan, S. Jiang, J. Tsang, M. I. Garin, C. Mottet, and R. I. Lechler In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance Blood, January 15, 2007; 109(2): 827 - 835. [Abstract] [Full Text] [PDF]
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M. Kallikourdis, K. G. Andersen, K. A. Welch, and A. G. Betz Alloantigen-enhanced accumulation of CCR5+ 'effector' regulatory T cells in the gravid uterus PNAS, January 9, 2007; 104(2): 594 - 599. [Abstract] [Full Text] [PDF]
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 H Keino, M Takeuchi, Y Usui, T Hattori, N Yamakawa, T Kezuka, J-I Sakai, and M Usui Supplementation of CD4+CD25+ regulatory T cells suppresses experimental autoimmune uveoretinitis Br J Ophthalmol, January 1, 2007; 91(1): 105 - 110. [Abstract] [Full Text] [PDF]
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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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M. Bodas, N. Jain, A. Awasthi, S. Martin, R. K. Penke Loka, D. Dandekar, D. Mitra, and B. Saha Inhibition of IL-2 Induced IL-10 Production as a Principle of Phase-Specific Immunotherapy J. Immunol., October 1, 2006; 177(7): 4636 - 4643. [Abstract] [Full Text] [PDF]
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L. Melencio, R. J. McKallip, H. Guan, R. Ramakrishnan, R. Jain, P. S. Nagarkatti, and M. Nagarkatti Role of CD4+CD25+ T regulatory cells in IL-2-induced vascular leak Int. Immunol., October 1, 2006; 18(10): 1461 - 1471. [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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