Brief Definitive Reports

Immunologic Self-Tolerance Maintained by CD25⁺CD4⁺ Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–associated Antigen 4

Correspondence to: Shimon Sakaguchi, Dept. of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Tel:81-75-751-3888 Fax:81-75-751-3820 E-mail:shimon{at}frontier.kyoto-u.ac.jp.

This report shows that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) plays a key role in T cell–mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific autoimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25⁺CD4⁺ T cells, which constitute 5–10% of peripheral CD4⁺ T cells. When the CD25⁺CD4⁺ T cells are stimulated via the T cell receptor in vitro, they potently suppress antigen-specific and polyclonal activation and proliferation of other T cells, including CTLA-4–deficient T cells, and blockade of CTLA-4 abrogates the suppression. CD28-deficient CD25⁺CD4⁺ T cells can also suppress normal T cells, indicating that CD28 is dispensable for activation of the regulatory T cells. Thus, the CD25⁺CD4⁺ regulatory T cell population engaged in dominant self-tolerance may require CTLA-4 but not CD28 as a costimulatory molecule for its functional activation. Furthermore, interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, presumably through affecting CD25⁺CD4⁺ T cell–mediated control of self-reactive T cells. This unique function of CTLA-4 could be exploited to potentiate T cell–mediated immunoregulation, and thereby to induce immunologic tolerance or to control autoimmunity.

Key Words: CTLA-4, autoimmune disease, regulatory T cell, CD25, self-tolerance

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• Hickman, S. P., Yang, J., Thomas, R. M., Wells, A. D., Turka, L. A. (2006). Defective Activation of Protein Kinase C and Ras-ERK Pathways Limits IL-2 Production and Proliferation by CD4+CD25+ Regulatory T Cells. J. Immunol. 177: 2186-2194 [Abstract] [Full Text]  
• Oida, T., Xu, L., Weiner, H. L., Kitani, A., Strober, W. (2006). TGF-beta-Mediated Suppression by CD4+CD25+ T Cells Is Facilitated by CTLA-4 Signaling. J. Immunol. 177: 2331-2339 [Abstract] [Full Text]  
• Nardelli, D. T., Warner, T. F., Callister, S. M., Schell, R. F. (2006). Anti-CD25 Antibody Treatment of Mice Vaccinated and Challenged with Borrelia spp. Does Not Exacerbate Arthritis but Inhibits Borreliacidal Antibody Production.. CVI 13: 884-891 [Abstract] [Full Text]  
• Beyer, M., Schultze, J. L. (2006). Regulatory T cells in cancer. Blood 108: 804-811 [Abstract] [Full Text]  
• Kocak, E., Lute, K., Chang, X., May, K. F. Jr., Exten, K. R., Zhang, H., Abdessalam, S. F., Lehman, A. M., Jarjoura, D., Zheng, P., Liu, Y. (2006). Combination Therapy with Anti-CTL Antigen-4 and Anti-4-1BB Antibodies Enhances Cancer Immunity and Reduces Autoimmunity.. Cancer Res. 66: 7276-7284 [Abstract] [Full Text]  
• Engelhardt, J. J., Sullivan, T. J., Allison, J. P. (2006). CTLA-4 Overexpression Inhibits T Cell Responses through a CD28-B7-Dependent Mechanism. J. Immunol. 177: 1052-1061 [Abstract] [Full Text]  
• Tsang, J. Y.-S., Camara, N. O. S., Eren, E., Schneider, H., Rudd, C., Lombardi, G., Lechler, R. (2006). Altered proximal T cell receptor (TCR) signaling in human CD4+CD25+ regulatory T cells. J. Leukoc. Biol. 80: 145-151 [Abstract] [Full Text]  
• Alard, P., Manirarora, J. N., Parnell, S. A., Hudkins, J. L., Clark, S. L., Kosiewicz, M. M. (2006). Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell-Mediated Regulation and Type 1 Diabetes Development in NOD Mice.. Diabetes 55: 2098-2105 [Abstract] [Full Text]  
• Wing, K., Fehervari, Z., Sakaguchi, S. (2006). Emerging possibilities in the development and function of regulatory T cells. Int Immunol 18: 991-1000 [Abstract] [Full Text]  
• Kaparakis, M., Laurie, K. L., Wijburg, O., Pedersen, J., Pearse, M., van Driel, I. R., Gleeson, P. A., Strugnell, R. A. (2006). CD4+ CD25+ Regulatory T Cells Modulate the T-Cell and Antibody Responses in Helicobacter-Infected BALB/c Mice.. Infect. Immun. 74: 3519-3529 [Abstract] [Full Text]  
• Beck, K. E., Blansfield, J. A., Tran, K. Q., Feldman, A. L., Hughes, M. S., Royal, R. E., Kammula, U. S., Topalian, S. L., Sherry, R. M., Kleiner, D., Quezado, M., Lowy, I., Yellin, M., Rosenberg, S. A., Yang, J. C. (2006). Enterocolitis in Patients With Cancer After Antibody Blockade of Cytotoxic T-Lymphocyte-Associated Antigen 4. JCO 24: 2283-2289 [Abstract] [Full Text]  
• Veldhoen, M., Moncrieffe, H., Hocking, R. J., Atkins, C. J., Stockinger, B. (2006). Modulation of Dendritic Cell Function by Naive and Regulatory CD4+ T Cells. J. Immunol. 176: 6202-6210 [Abstract] [Full Text]  
• Beyer, M., Kochanek, M., Giese, T., Endl, E., Weihrauch, M. R., Knolle, P. A., Classen, S., Schultze, J. L. (2006). In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma. Blood 107: 3940-3949 [Abstract] [Full Text]  
• Liu, H., Komai-Koma, M., Xu, D., Liew, F. Y. (2006). Toll-like receptor 2 signaling modulates the functions of CD4+CD25+ regulatory T cells. Proc. Natl. Acad. Sci. USA 103: 7048-7053 [Abstract] [Full Text]  
• Coenen, J. J. A., Koenen, H. J. P. M., van Rijssen, E., Boon, L., Joosten, I., Hilbrands, L. B. (2006). CTLA-4 Engagement and Regulatory CD4+CD25+ T Cells Independently Control CD8+-Mediated Responses under Costimulation Blockade. J. Immunol. 176: 5240-5246 [Abstract] [Full Text]  
• Antony, P. A., Paulos, C. M., Ahmadzadeh, M., Akpinarli, A., Palmer, D. C., Sato, N., Kaiser, A., Heinrichs, C., Klebanoff, C. A., Tagaya, Y., Restifo, N. P. (2006). Interleukin-2-Dependent Mechanisms of Tolerance and Immunity In Vivo. J. Immunol. 176: 5255-5266 [Abstract] [Full Text]  
• Kanai, T., Tanimoto, K., Nemoto, Y., Fujii, R., Makita, S., Totsuka, T., Watanabe, M. (2006). Naturally arising CD4+CD25+ regulatory T cells suppress the expansion of colitogenic CD4+CD44highCD62L- effector memory T cells. Am. J. Physiol. Gastrointest. Liver Physiol. 290: G1051-G1058 [Abstract] [Full Text]  
• Gonzalez-Rey, E., Chorny, A., Fernandez-Martin, A., Ganea, D., Delgado, M. (2006). Vasoactive intestinal peptide generates human tolerogenic dendritic cells that induce CD4 and CD8 regulatory T cells. Blood 107: 3632-3638 [Abstract] [Full Text]  
• Yang, Z.-Z., Novak, A. J., Stenson, M. J., Witzig, T. E., Ansell, S. M. (2006). Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood 107: 3639-3646 [Abstract] [Full Text]  

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