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Science 317 (5838): 627-629

Copyright © 2007 by the American Association for the Advancement of Science

Emerging Challenges in Regulatory T Cell Function and Biology

Shimon Sakaguchi1, and Fiona Powrie2

Abstract: Much progress has been made in understanding how the immune system is regulated, with a great deal of recent interest in naturally occurring CD4+ regulatory T cells that actively engage in the maintenance of immunological self-tolerance and immune homeostasis. The challenge ahead for immunologists is the further elucidation of the molecular and cellular processes that govern the development and function of these cells. From this, exciting possibilities are emerging for the manipulation of regulatory T cell pathways in treating immunological diseases and suppressing or augmenting physiological immune responses.

1 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
2 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.

Regulatory T Cells Suppress the Late Phase of the Immune Response in Lymph Nodes through P-Selectin Glycoprotein Ligand-1.
S. Angiari, B. Rossi, L. Piccio, B. H. Zinselmeyer, S. Budui, E. Zenaro, V. Della Bianca, S. D. Bach, E. Scarpini, M. Bolomini-Vittori, et al. (2013)
J. Immunol. 191, 5489-5500
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Effective Anti-Neu-Initiated Antitumor Responses Require the Complex Role of CD4+ T Cells.
E. D. Mortenson, S. Park, Z. Jiang, S. Wang, and Y.-X. Fu (2013)
Clin. Cancer Res. 19, 1476-1486
   Abstract »    Full Text »    PDF »
Inhibition of S-phase kinase-associated protein 2 (Skp2) reprograms and converts diabetogenic T cells to Foxp3+ regulatory T cells.
D. Wang, H. Qin, W. Du, Y.-W. Shen, W.-H. Lee, A. D. Riggs, and C.-P. Liu (2012)
PNAS 109, 9493-9498
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Foxp3 Expression Patterns in Microscopic Colitides: A Clinicopathologic Study of 69 Patients.
S. Bai, G. P. Siegal, and N. C. Jhala (2012)
Am J Clin Pathol 137, 931-936
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Roles of LAG3 and EGR2 in regulatory T cells.
T. Okamura, K. Fujio, S. Sumitomo, and K. Yamamoto (2012)
Ann Rheum Dis 71, i96-i100
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Dietary Plasma Proteins Modulate the Adaptive Immune Response in Mice with Acute Lung Inflammation.
M. Maijo, L. Miro, J. Polo, J. Campbell, L. Russell, J. Crenshaw, E. Weaver, M. Moreto, and A. Perez-Bosque (2012)
J. Nutr. 142, 264-270
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Loss of Intra-Islet CD20 Expression May Complicate Efficacy of B-Cell-Directed Type 1 Diabetes Therapies.
D. V. Serreze, H. D. Chapman, M. Niens, R. Dunn, M. R. Kehry, J. P. Driver, M. Haller, C. Wasserfall, and M. A. Atkinson (2011)
Diabetes 60, 2914-2921
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A Role for IL-27 in Limiting T Regulatory Cell Populations.
E. D. Tait Wojno, N. Hosken, J. S. Stumhofer, A. C. O'Hara, E. Mauldin, Q. Fang, L. A. Turka, S. D. Levin, and C. A. Hunter (2011)
J. Immunol. 187, 266-273
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Noncanonical K27-Linked Polyubiquitination of TIEG1 Regulates Foxp3 Expression and Tumor Growth.
D.-J. Peng, M. Zeng, R. Muromoto, T. Matsuda, K. Shimoda, M. Subramaniam, T. C. Spelsberg, W.-Z. Wei, and K. Venuprasad (2011)
J. Immunol. 186, 5638-5647
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CD4+CD25+ Regulatory T Cells Prevent Type 1 Diabetes Preceded by Dendritic Cell-Dominant Invasive Insulitis by Affecting Chemotaxis and Local Invasiveness of Dendritic Cells.
M.-H. Lee, W.-H. Lee, I. Todorov, and C.-P. Liu (2010)
J. Immunol. 185, 2493-2501
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APC Activation by IFN-{alpha} Decreases Regulatory T Cell and Enhances Th Cell Functions.
L. Pace, S. Vitale, B. Dettori, C. Palombi, V. La Sorsa, F. Belardelli, E. Proietti, and G. Doria (2010)
J. Immunol. 184, 5969-5979
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Distinct Roles for CCR4 and CXCR3 in the Recruitment and Positioning of Regulatory T Cells in the Inflamed Human Liver.
Y. H. Oo, C. J. Weston, P. F. Lalor, S. M. Curbishley, D. R. Withers, G. M. Reynolds, S. Shetty, J. Harki, J. C. Shaw, B. Eksteen, et al. (2010)
J. Immunol. 184, 2886-2898
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Granzyme B is not required for regulatory T cell-mediated suppression of graft-versus-host disease.
S. F. Cai, X. Cao, A. Hassan, T. A. Fehniger, and T. J. Ley (2010)
Blood 115, 1669-1677
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Myelin Basic Protein Priming Reduces the Expression of Foxp3 in T Cells via Nitric Oxide.
S. Brahmachari and K. Pahan (2010)
J. Immunol. 184, 1799-1809
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Defects in IL-2R Signaling Contribute to Diminished Maintenance of FOXP3 Expression in CD4+CD25+ Regulatory T-Cells of Type 1 Diabetic Subjects.
S. A. Long, K. Cerosaletti, P. L. Bollyky, M. Tatum, H. Shilling, S. Zhang, Z.-Y. Zhang, C. Pihoker, S. Sanda, C. Greenbaum, et al. (2010)
Diabetes 59, 407-415
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Immunostimulatory RNA Blocks Suppression by Regulatory T Cells.
D. Anz, V. H. Koelzer, S. Moder, R. Thaler, T. Schwerd, K. Lahl, T. Sparwasser, R. Besch, H. Poeck, V. Hornung, et al. (2010)
J. Immunol. 184, 939-946
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CD4+ T Cells and Lactobacillus casei Control Relapsing Colitis Mediated by CD8+ T Cells.
F. Hacini-Rachinel, S. Nancey, G. Boschetti, F. Sardi, R. Doucet-Ladeveze, P.-Y. Durand, B. Flourie, and D. Kaiserlian (2009)
J. Immunol. 183, 5477-5486
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Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide.
D. Pozo, P. Anderson, and E. Gonzalez-Rey (2009)
J. Immunol. 183, 4346-4359
   Abstract »    Full Text »    PDF »
CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2.
T. Okamura, K. Fujio, M. Shibuya, S. Sumitomo, H. Shoda, S. Sakaguchi, and K. Yamamoto (2009)
PNAS 106, 13974-13979
   Abstract »    Full Text »    PDF »
Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease.
M. Semitekolou, T. Alissafi, M. Aggelakopoulou, E. Kourepini, H. H. Kariyawasam, A. B. Kay, D. S. Robinson, C. M. Lloyd, V. Panoutsakopoulou, and G. Xanthou (2009)
J. Exp. Med. 206, 1769-1785
   Abstract »    Full Text »    PDF »
Suppression of Regulatory T Cells by IL-12p40 Homodimer via Nitric Oxide.
S. Brahmachari and K. Pahan (2009)
J. Immunol. 183, 2045-2058
   Abstract »    Full Text »    PDF »
A brief review of potential mechanisms of immune reconstitution inflammatory syndrome in HIV following antiretroviral therapy.
S. Mori and P. Levin (2009)
International Journal of STD & AIDS 20, 447-452
   Abstract »    Full Text »    PDF »
Regulatory T-cell status in red cell alloimmunized responder and nonresponder mice.
W. Bao, J. Yu, S. Heck, and K. Yazdanbakhsh (2009)
Blood 113, 5624-5627
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Epigenetic Regulation of Foxp3 Expression in Regulatory T Cells by DNA Methylation.
G. Lal, N. Zhang, W. van der Touw, Y. Ding, W. Ju, E. P. Bottinger, S. P. Reid, D. E. Levy, and J. S. Bromberg (2009)
J. Immunol. 182, 259-273
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In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure.
F. Meiler, J. Zumkehr, S. Klunker, B. Ruckert, C. A. Akdis, and M. Akdis (2008)
J. Exp. Med. 205, 2887-2898
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Cutting Edge: In Vivo Trogocytosis as a Mechanism of Double Negative Regulatory T Cell-Mediated Antigen-Specific Suppression.
M. S. Ford McIntyre, K. J. Young, J. Gao, B. Joe, and L. Zhang (2008)
J. Immunol. 181, 2271-2275
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Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation.
Y. Onishi, Z. Fehervari, T. Yamaguchi, and S. Sakaguchi (2008)
PNAS 105, 10113-10118
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Functional Analysis of Effector and Regulatory T Cells in a Parasitic Nematode Infection.
S. Rausch, J. Huehn, D. Kirchhoff, J. Rzepecka, C. Schnoeller, S. Pillai, C. Loddenkemper, A. Scheffold, A. Hamann, R. Lucius, et al. (2008)
Infect. Immun. 76, 1908-1919
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IL-10 and Natural Regulatory T Cells: Two Independent Anti-Inflammatory Mechanisms in Herpes Simplex Virus-Induced Ocular Immunopathology.
P. P. Sarangi, S. Sehrawat, S. Suvas, and B. T. Rouse (2008)
J. Immunol. 180, 6297-6306
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Assessment of Bet v 1-Specific CD4+ T Cell Responses in Allergic and Nonallergic Individuals Using MHC Class II Peptide Tetramers.
L. Van Overtvelt, E. Wambre, B. Maillere, E. von Hofe, A. Louise, A. M. Balazuc, B. Bohle, D. Ebo, C. Leboulaire, G. Garcia, et al. (2008)
J. Immunol. 180, 4514-4522
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Division of Labor with a Workforce of One: Challenges in Specifying Effector and Memory T Cell Fate.
S. L. Reiner, F. Sallusto, and A. Lanzavecchia (2007)
Science 317, 622-625
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