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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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Cancer Prevention Research 3, 1265-1276
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Endotoxin tolerance attenuates airway allergic inflammation in model mice by suppression of the T-cell stimulatory effect of dendritic cells.
H. Matsushita, S. Ohta, H. Shiraishi, S. Suzuki, K. Arima, S. Toda, H. Tanaka, H. Nagai, M. Kimoto, A. Inokuchi, et al. (2010)
Int. Immunol. 22, 739-747
   Abstract »    Full Text »    PDF »
T-cell regulation by casitas B-lineage lymphoma (Cblb) is a critical failsafe against autoimmune disease due to autoimmune regulator (Aire) deficiency.
C. E. Teh, S. R. Daley, A. Enders, and C. C. Goodnow (2010)
PNAS 107, 14709-14714
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Much Ado about Adenosine: Adenosine Synthesis and Function in Regulatory T Cell Biology.
P. B. Ernst, J. C. Garrison, and L. F. Thompson (2010)
J. Immunol. 185, 1993-1998
   Abstract »    Full Text »    PDF »
Foxp3+ CD4 Regulatory T Cells Limit Pulmonary Immunopathology by Modulating the CD8 T Cell Response during Respiratory Syncytial Virus Infection.
R. B. Fulton, D. K. Meyerholz, and S. M. Varga (2010)
J. Immunol. 185, 2382-2392
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Pathogen-specific regulatory T cells delay the arrival of effector T cells in the lung during early tuberculosis.
S. Shafiani, G. Tucker-Heard, A. Kariyone, K. Takatsu, and K. B. Urdahl (2010)
J. Exp. Med. 207, 1409-1420
   Abstract »    Full Text »    PDF »
Genetics of Type 1 Diabetes: What's Next?.
F. Pociot, B. Akolkar, P. Concannon, H. A. Erlich, C. Julier, G. Morahan, C. R. Nierras, J. A. Todd, S. S. Rich, and J. Nerup (2010)
Diabetes 59, 1561-1571
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Role Played by CD4+ FOXP3+ Regulatory T Cells in Suppression of Host Responses to Haemophilus ducreyi during Experimental Infection of Human Volunteers.
W. Li, K. Tenner-Racz, P. Racz, D. M. Janowicz, K. R. Fortney, B. P. Katz, and S. M. Spinola (2010)
The Journal of Infectious Disease 201, 1839-1848
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