Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4

By Takeshi Takahashi, Tomoyuki Tagami, S. Yamazaki, T. Uede, J. Shimizu, N. Sakaguchi, T. Mak, Shimon Sakaguchi. Journal of Experimental Medicine, 2000

2,468 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/870b9c4329aeab02f0cc591ffcafacbb4ebbdf6e

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Shimon Sakaguchi
2. James P. Allison
3. W. Zou
4. A. O’Garra
5. J. Wolchok
6. E. Shevach
7. G. Freeman
8. P. Vieira

In Oncology

1. James P. Allison
2. J. Wolchok
3. G. Freeman
4. E. Shevach
5. Ton N. Schumacher
6. W. Zou
7. Shimon Sakaguchi
8. Sergio A. Quezada

Citations in the corpus

• Human Cd25+Cd4+ T Regulatory Cells Suppress Naive and Memory T Cell Proliferation and Can Be Expanded in Vitro without Loss of Function (2001, background): “1296 Human CD25 CD4 T Regulatory Cells to suppress immune responses in vivo (10, 18).”
• Molecular Mechanisms of Treg-Mediated T Cell Suppression (2012, background): “A role for CTLA-4 in suppression in vivo has been suggested, since CTLA-4 deficiency or blockade in mice results in spontaneous autoimmunity, which can be ameliorated by Tregs (Bachmann et al., 1999; Takahashi et al., 2000).”
• Regulatory T cells mediate maternal tolerance to the fetus (2004, background): “Regulatory T cells express the cell surface marker CTLA-4 (ref”