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.
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17 July 2000
Brief Definitive Report|
July 17 2000
Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4
Takeshi Takahashi,
Takeshi Takahashi
aDepartment of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
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Tomoyuki Tagami,
Tomoyuki Tagami
bDepartment of Immunopathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
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Sayuri Yamazaki,
Sayuri Yamazaki
aDepartment of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
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Toshimitsu Uede,
Toshimitsu Uede
cInstitute of Immunological Science, Hokkaido University, Sapporo 060-8638, Japan
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Jun Shimizu,
Jun Shimizu
bDepartment of Immunopathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
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Noriko Sakaguchi,
Noriko Sakaguchi
aDepartment of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
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Tak W. Mak,
Tak W. Mak
dAmgen Institute, Ontario Cancer Institute, Department of Immunology and Medical Biophysics, University of Toronto, Toronto M5G2C1, Canada
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Shimon Sakaguchi
Shimon Sakaguchi
aDepartment of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
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Takeshi Takahashi
aDepartment of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
Tomoyuki Tagami
bDepartment of Immunopathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
Sayuri Yamazaki
aDepartment of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
Toshimitsu Uede
cInstitute of Immunological Science, Hokkaido University, Sapporo 060-8638, Japan
Jun Shimizu
bDepartment of Immunopathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
Noriko Sakaguchi
aDepartment of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
Tak W. Mak
dAmgen Institute, Ontario Cancer Institute, Department of Immunology and Medical Biophysics, University of Toronto, Toronto M5G2C1, Canada
Shimon Sakaguchi
aDepartment of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
Received:
February 10 2000
Revision Requested:
May 23 2000
Accepted:
June 08 2000
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Exp Med (2000) 192 (2): 303–310.
Article history
Received:
February 10 2000
Revision Requested:
May 23 2000
Accepted:
June 08 2000
Citation
Takeshi Takahashi, Tomoyuki Tagami, Sayuri Yamazaki, Toshimitsu Uede, Jun Shimizu, Noriko Sakaguchi, Tak W. Mak, Shimon Sakaguchi; Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4. J Exp Med 17 July 2000; 192 (2): 303–310. doi: https://doi.org/10.1084/jem.192.2.303
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