Published online 17 July 2000.
© The Rockefeller University Press, 0022-1007/2000/7/303/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 2, July 17, 2000 303-310
Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4
Takeshi Takahashia,
Tomoyuki Tagamib,
Sayuri Yamazakia,
Toshimitsu Uedec,
Jun Shimizub,
Noriko Sakaguchia,
Tak W. Makd, and
Shimon Sakaguchia
a Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
b Department of Immunopathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
c Institute of Immunological Science, Hokkaido University, Sapporo 060-8638, Japan
d Amgen Institute, Ontario Cancer Institute, Department of Immunology and Medical Biophysics, University of Toronto, Toronto M5G2C1, Canada
Dept. of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.81-75-751-382081-75-751-3888
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
© 2000 The Rockefeller University Press
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