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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}

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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.
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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
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