Brief Definitive Report

Ex Vivo Isolation and Characterization of CD4⁺CD25⁺ T Cells with Regulatory Properties from Human Blood

Correspondence to: Gerold Schuler, Department of Dermatology, University of Erlangen-Nuremberg, Hartmannstrasse 14, 91052 Erlangen, Germany. Tel:49-9131-853-3661 Fax:49-9131-853-6175 E-mail:schuler{at}derma.med.uni-erlangen.de.

It has been known for years that rodents harbor a unique population of CD4⁺CD25⁺ "professional" regulatory/suppressor T cells that is crucial for the prevention of spontaneous autoimmune diseases. Here we demonstrate that CD4⁺CD25⁺CD45RO⁺ T cells (mean 6% of CD4⁺ T cells) are present in the blood of adult healthy volunteers. In contrast to previous reports, these CD4⁺CD25⁺ T cells do not constitute conventional memory cells but rather regulatory cells exhibiting properties identical to their rodent counterparts. Cytotoxic T lymphocyte–associated antigen (CTLA)-4 (CD152), for example, which is essential for the in vivo suppressive activity of CD4⁺CD25⁺ T cells, was constitutively expressed, and remained strongly upregulated after stimulation. The cells were nonproliferative to stimulation via their T cell receptor for antigen, but the anergic state was partially reversed by interleukin (IL)-2 and IL-15. Upon stimulation with allogeneic (but not syngeneic) mature dendritic cells or platebound anti-CD3 plus anti-CD28 the CD4⁺CD25⁺ T cells released IL-10, and in coculture experiments suppressed the activation and proliferation of CD4⁺ and CD8⁺ T cells. Suppression proved IL-10 independent, yet contact dependent as in the mouse. The identification of regulatory CD4⁺CD25⁺ T cells has important implications for the study of tolerance in man, notably in the context of autoimmunity, transplantation, and cancer.

Key Words: CD4⁺CD25⁺ T cells, regulatory T cells, immune tolerance, anergy, dendritic cells

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• Sugiyama, H., Gyulai, R., Toichi, E., Garaczi, E., Shimada, S., Stevens, S. R., McCormick, T. S., Cooper, K. D. (2005). Dysfunctional Blood and Target Tissue CD4+CD25high Regulatory T Cells in Psoriasis: Mechanism Underlying Unrestrained Pathogenic Effector T Cell Proliferation. J. Immunol. 174: 164-173 [Abstract] [Full Text]  
• Braat, H., van den Brande, J., van Tol, E., Hommes, D., Peppelenbosch, M., van Deventer, S. (2004). Lactobacillus rhamnosus induces peripheral hyporesponsiveness in stimulated CD4+ T cells via modulation of dendritic cell function. Am. J. Clin. Nutr. 80: 1618-1625 [Abstract] [Full Text]  
• Zou, L., Barnett, B., Safah, H., LaRussa, V. F., Evdemon-Hogan, M., Mottram, P., Wei, S., David, O., Curiel, T. J., Zou, W. (2004). Bone Marrow Is a Reservoir for CD4+CD25+ Regulatory T Cells that Traffic through CXCL12/CXCR4 Signals. Cancer Res. 64: 8451-8455 [Abstract] [Full Text]  
• van Santen, H.-M., Benoist, C., Mathis, D. (2004). Number of T Reg Cells That Differentiate Does Not Increase upon Encounter of Agonist Ligand on Thymic Epithelial Cells. J. Exp. Med. 200: 1221-1230 [Abstract] [Full Text]  
• Weiss, L., Donkova-Petrini, V., Caccavelli, L., Balbo, M., Carbonneil, C., Levy, Y. (2004). Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood 104: 3249-3256 [Abstract] [Full Text]  
• Xystrakis, E., Dejean, A. S., Bernard, I., Druet, P., Liblau, R., Gonzalez-Dunia, D., Saoudi, A. (2004). Identification of a novel natural regulatory CD8 T-cell subset and analysis of its mechanism of regulation. Blood 104: 3294-3301 [Abstract] [Full Text]  
• Nardelli, D. T., Burchill, M. A., England, D. M., Torrealba, J., Callister, S. M., Schell, R. F. (2004). Association of CD4+ CD25+ T Cells with Prevention of Severe Destructive Arthritis in Borrelia burgdorferi-Vaccinated and Challenged Gamma Interferon-Deficient Mice Treated with Anti-Interleukin-17 Antibody. CVI 11: 1075-1084 [Abstract] [Full Text]  
• Yagi, H., Nomura, T., Nakamura, K., Yamazaki, S., Kitawaki, T., Hori, S., Maeda, M., Onodera, M., Uchiyama, T., Fujii, S., Sakaguchi, S. (2004). Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol 16: 1643-1656 [Abstract] [Full Text]  
• Moseman, E. A., Liang, X., Dawson, A. J., Panoskaltsis-Mortari, A., Krieg, A. M., Liu, Y.-J., Blazar, B. R., Chen, W. (2004). Human Plasmacytoid Dendritic Cells Activated by CpG Oligodeoxynucleotides Induce the Generation of CD4+CD25+ Regulatory T Cells. J. Immunol. 173: 4433-4442 [Abstract] [Full Text]  
• Thornton, C. A., Upham, J. W., Wikstrom, M. E., Holt, B. J., White, G. P., Sharp, M. J., Sly, P. D., Holt, P. G. (2004). Functional Maturation of CD4+CD25+CTLA4+CD45RA+ T Regulatory Cells in Human Neonatal T Cell Responses to Environmental Antigens/Allergens. J. Immunol. 173: 3084-3092 [Abstract] [Full Text]  
• Makita, S., Kanai, T., Oshima, S., Uraushihara, K., Totsuka, T., Sawada, T., Nakamura, T., Koganei, K., Fukushima, T., Watanabe, M. (2004). CD4+CD25bright T Cells in Human Intestinal Lamina Propria as Regulatory Cells. J. Immunol. 173: 3119-3130 [Abstract] [Full Text]  
• Zheng, G., Wang, B., Chen, A. (2004). The 4-1BB Costimulation Augments the Proliferation of CD4+CD25+ Regulatory T Cells. J. Immunol. 173: 2428-2434 [Abstract] [Full Text]  
• Kinter, A. L., Hennessey, M., Bell, A., Kern, S., Lin, Y., Daucher, M., Planta, M., McGlaughlin, M., Jackson, R., Ziegler, S. F., Fauci, A. S. (2004). CD25+CD4+ Regulatory T Cells from the Peripheral Blood of Asymptomatic HIV-infected Individuals Regulate CD4+ and CD8+ HIV-specific T Cell Immune Responses In Vitro and Are Associated with Favorable Clinical Markers of Disease Status. J. Exp. Med. 200: 331-343 [Abstract] [Full Text]  
• Ehrenstein, M. R., Evans, J. G., Singh, A., Moore, S., Warnes, G., Isenberg, D. A., Mauri, C. (2004). Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNF{alpha} Therapy. J. Exp. Med. 200: 277-285 [Abstract] [Full Text]  
• Hoffmann, P., Eder, R., Kunz-Schughart, L. A., Andreesen, R., Edinger, M. (2004). Large-scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells. Blood 104: 895-903 [Abstract] [Full Text]  

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