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Science 322 (5899): 271-275

Copyright © 2008 by the American Association for the Advancement of Science

CTLA-4 Control over Foxp3+ Regulatory T Cell Function

Kajsa Wing,1* Yasushi Onishi,1,2 Paz Prieto-Martin,1 Tomoyuki Yamaguchi,1 Makoto Miyara,1 Zoltan Fehervari,1 Takashi Nomura,1 Shimon Sakaguchi1,3,4{dagger}

Abstract: Naturally occurring Foxp3+CD4+ regulatory T cells (Tregs) are essential for maintaining immunological self-tolerance and immune homeostasis. Here, we show that a specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) in Tregs results in spontaneous development of systemic lymphoproliferation, fatal T cell–mediated autoimmune disease, and hyperproduction of immunoglobulin E in mice, and it also produces potent tumor immunity. Treg-specific CTLA-4 deficiency impairs in vivo and in vitro suppressive function of Tregs—in particular, Treg-mediated down-regulation of CD80 and CD86 expression on dendritic cells. Thus, natural Tregs may critically require CTLA-4 to suppress immune responses by affecting the potency of antigen-presenting cells to activate other T cells.

1 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
2 Department of Rheumatology and Haematology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
3 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan.
4 Laboratory of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.

* Present address: Department of Medical Inflammation Research, Karolinska Institute, Stockholm 17177, Sweden.

{dagger} To whom correspondence should be addressed. E-mail: shimon{at}frontier.kyoto-u.ac.jp


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Foxp3+ regulatory T cells exert asymmetric control over murine helper responses by inducing Th2 cell apoptosis.
L. Tian, J. A. Altin, L. E. Makaroff, D. Franckaert, M. C. Cook, C. C. Goodnow, J. Dooley, and A. Liston (2011)
Blood 118, 1845-1853
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Cytotoxic T-Lymphocyte-Associated Antigen-4.
A. K. S. Salama and F. S. Hodi (2011)
Clin. Cancer Res. 17, 4622-4628
   Abstract »    Full Text »    PDF »
The Soluble CTLA-4 Splice Variant Protects From Type 1 Diabetes and Potentiates Regulatory T-Cell Function.
K. D. Gerold, P. Zheng, D. B. Rainbow, A. Zernecke, L. S. Wicker, and S. Kissler (2011)
Diabetes 60, 1955-1963
   Abstract »    Full Text »    PDF »

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