Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 10 October 2008:
Vol. 322. no. 5899, pp. 271 - 275
DOI: 10.1126/science.1160062
Prev | Table of Contents | Next

Reports

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}

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Regulatory T Cell (Treg) Subsets Return in Patients with Refractory Lupus following Stem Cell Transplantation, and TGF-{beta}-Producing CD8+ Treg Cells Are Associated with Immunological Remission of Lupus.
L. Zhang, A. M. Bertucci, R. Ramsey-Goldman, R. K. Burt, and S. K. Datta (2009)
J. Immunol. 183, 6346-6358
   Abstract »    Full Text »    PDF »
Superagonistic CD28 stimulation of allogeneic T cells protects from acute graft-versus-host disease.
N. Beyersdorf, X. Ding, T. Hunig, and T. Kerkau (2009)
Blood 114, 4575-4582
   Abstract »    Full Text »    PDF »
1,25-Dihydroxyvitamin D3 and IL-2 Combine to Inhibit T Cell Production of Inflammatory Cytokines and Promote Development of Regulatory T Cells Expressing CTLA-4 and FoxP3.
L. E. Jeffery, F. Burke, M. Mura, Y. Zheng, O. S. Qureshi, M. Hewison, L. S. K. Walker, D. A. Lammas, K. Raza, and D. M. Sansom (2009)
J. Immunol. 183, 5458-5467
   Abstract »    Full Text »    PDF »
Constitutive Expression of IDO by Dendritic Cells of Mesenteric Lymph Nodes: Functional Involvement of the CTLA-4/B7 and CCL22/CCR4 Interactions.
T. Onodera, M. H. Jang, Z. Guo, M. Yamasaki, T. Hirata, Z. Bai, N. M. Tsuji, D. Nagakubo, O. Yoshie, S. Sakaguchi, et al. (2009)
J. Immunol. 183, 5608-5614
   Abstract »    Full Text »    PDF »
Nonfunctional Regulatory T Cells and Defective Control of Th2 Cytokine Production in Natural Scurfy Mutant Mice.
K. Lahl, C. T. Mayer, T. Bopp, J. Huehn, C. Loddenkemper, G. Eberl, G. Wirnsberger, K. Dornmair, R. Geffers, E. Schmitt, et al. (2009)
J. Immunol. 183, 5662-5672
   Abstract »    Full Text »    PDF »
Ectopically expressed PIR-B on T cells constitutively binds to MHC class I and attenuates T helper type 1 responses.
M. Imada, K. Masuda, R. Satoh, Y. Ito, Y. Goto, T. Matsuoka, S. Endo, A. Nakamura, H. Kawamoto, and T. Takai (2009)
Int. Immunol. 21, 1151-1161
   Abstract »    Full Text »    PDF »
Regulatory T cells: how do they suppress immune responses?.
S. Sakaguchi, K. Wing, Y. Onishi, P. Prieto-Martin, and T. Yamaguchi (2009)
Int. Immunol. 21, 1105-1111
   Abstract »    Full Text »    PDF »
Cutting Edge: Dab2 Is a FOXP3 Target Gene Required for Regulatory T Cell Function.
N. Jain, H. Nguyen, R. H. Friedline, N. Malhotra, M. Brehm, M. Koyanagi, M. Bix, J. A. Cooper, C. A. Chambers, and J. Kang (2009)
J. Immunol. 183, 4192-4196
   Abstract »    Full Text »    PDF »
De Novo Generation and Enhanced Suppression of Human CD4+CD25+ Regulatory T Cells by Retinoic Acid.
J. Wang, T. W. J. Huizinga, and R. E. M. Toes (2009)
J. Immunol. 183, 4119-4126
   Abstract »    Full Text »    PDF »
Superantigen-Activated Regulatory T Cells Inhibit the Migration of Innate Immune Cells and the Differentiation of Naive T Cells.
Y. Tanriver, A. Martin-Fontecha, K. Ratnasothy, G. Lombardi, and R. Lechler (2009)
J. Immunol. 183, 2946-2956
   Abstract »    Full Text »    PDF »
Eos Mediates Foxp3-Dependent Gene Silencing in CD4+ Regulatory T Cells.
F. Pan, H. Yu, E. V. Dang, J. Barbi, X. Pan, J. F. Grosso, D. Jinasena, S. M. Sharma, E. M. McCadden, D. Getnet, et al. (2009)
Science 325, 1142-1146
   Abstract »    Full Text »    PDF »
Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies.
K. S. Peggs, S. A. Quezada, C. A. Chambers, A. J. Korman, and J. P. Allison (2009)
J. Exp. Med. 206, 1717-1725
   Abstract »    Full Text »    PDF »
What Is the Role of Cytotoxic T Lymphocyte-Associated Antigen 4 Blockade in Patients with Metastatic Melanoma?.
C. Robert and F. Ghiringhelli (2009)
Oncologist 14, 848-861
   Abstract »    Full Text »    PDF »
Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity.
C. Schmidl, M. Klug, T. J. Boeld, R. Andreesen, P. Hoffmann, M. Edinger, and M. Rehli (2009)
Genome Res. 19, 1165-1174
   Abstract »    Full Text »    PDF »
Fc Receptor-Like 3 Protein Expressed on IL-2 Nonresponsive Subset of Human Regulatory T Cells.
S. Nagata, T. Ise, and I. Pastan (2009)
J. Immunol. 182, 7518-7526
   Abstract »    Full Text »    PDF »
Molecular orchestration of differentiation and function of regulatory T cells.
L.-F. Lu and A. Rudensky (2009)
Genes & Dev. 23, 1270-1282
   Abstract »    Full Text »    PDF »
An engineered lipocalin specific for CTLA-4 reveals a combining site with structural and conformational features similar to antibodies.
D. Schonfeld, G. Matschiner, L. Chatwell, S. Trentmann, H. Gille, M. Hulsmeyer, N. Brown, P. M. Kaye, S. Schlehuber, A. M. Hohlbaum, et al. (2009)
PNAS 106, 8198-8203
   Abstract »    Full Text »    PDF »
PD-1 and CTLA-4 Inhibitory Cosignaling Pathways in HIV Infection and the Potential for Therapeutic Intervention.
D. E. Kaufmann and B. D. Walker (2009)
J. Immunol. 182, 5891-5897
   Abstract »    Full Text »    PDF »
Tumor Regulatory T Cells Potently Abrogate Antitumor Immunity.
Z. Liu, J. H. Kim, L. D. Falo Jr., and Z. You (2009)
J. Immunol. 182, 6160-6167
   Abstract »    Full Text »    PDF »
Sialoadhesin-Positive Macrophages Bind Regulatory T Cells, Negatively Controlling Their Expansion and Autoimmune Disease Progression.
C. Wu, U. Rauch, E. Korpos, J. Song, K. Loser, P. R. Crocker, and L. M. Sorokin (2009)
J. Immunol. 182, 6508-6516
   Abstract »    Full Text »    PDF »
Surveillance of Antigen-Presenting Cells by CD4+CD25+ Regulatory T Cells in Autoimmunity: Immunopathogenesis and Therapeutic Implications.
S. Andre, D. F. Tough, S. Lacroix-Desmazes, S. V. Kaveri, and J. Bayry (2009)
Am. J. Pathol. 174, 1575-1587
   Abstract »    Full Text »    PDF »
Differential control of allo-antigen-specific regulatory T cells and effector T cells by anti-CD4 and other agents in establishing transplantation tolerance.
K. Nagahama, Z. Fehervari, T. Oida, T. Yamaguchi, O. Ogawa, and S. Sakaguchi (2009)
Int. Immunol. 21, 379-391
   Abstract »    Full Text »    PDF »
Regulatory T Cells: The Cunning Fox and Its Clinical Application.
D. S. Game, X. Cao, and S. Jiang (2008)
Science Signaling 1, mr3
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)