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Originally published in Science Express on 14 June 2007
Science 13 July 2007:
Vol. 317. no. 5835, pp. 256 - 260
DOI: 10.1126/science.1145697
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Reports

Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid

Daniel Mucida, Yunji Park, Gisen Kim, Olga Turovskaya, Iain Scott, Mitchell Kronenberg, Hilde Cheroutre*

The cytokine transforming growth factor–ß (TGF-ß) converts naïve T cells into regulatory T (Treg) cells that prevent autoimmunity. However, in the presence of interleukin-6 (IL-6), TGF-ß has also been found to promote the differentiation of naïve T lymphocytes into proinflammatory IL-17 cytokine-producing T helper 17 (TH17) cells, which promote autoimmunity and inflammation. This raises the question of how TGF-ß can generate such distinct outcomes. We identified the vitamin A metabolite retinoic acid as a key regulator of TGF-ß–dependent immune responses, capable of inhibiting the IL-6–driven induction of proinflammatory TH17 cells and promoting anti-inflammatory Treg cell differentiation. These findings indicate that a common metabolite can regulate the balance between pro- and anti-inflammatory immunity.

La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.

* To whom correspondence should be addressed. E-mail: hilde{at}liai.org

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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M. M.W. Chong, J. P. Rasmussen, A. Y. Rudensky, and D. R. Littman (2008)
J. Exp. Med. 205, 2005-2017
   Abstract »    Full Text »    PDF »
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D. Zhao, C. Zhang, T. Yi, C.-L. Lin, I. Todorov, F. Kandeel, S. Forman, and D. Zeng (2008)
Blood 112, 2129-2138
   Abstract »    Full Text »    PDF »
Retinoic Acid Increases Foxp3+ Regulatory T Cells and Inhibits Development of Th17 Cells by Enhancing TGF-{beta}-Driven Smad3 Signaling and Inhibiting IL-6 and IL-23 Receptor Expression.
S. Xiao, H. Jin, T. Korn, S. M. Liu, M. Oukka, B. Lim, and V. K. Kuchroo (2008)
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   Abstract »    Full Text »    PDF »
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E. Godebu, D. Summers-Torres, M. M. Lin, B. J. G. Baaten, and L. M. Bradley (2008)
J. Immunol. 181, 1798-1805
   Abstract »    Full Text »    PDF »
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C. S. Lages, I. Suffia, P. A. Velilla, B. Huang, G. Warshaw, D. A. Hildeman, Y. Belkaid, and C. Chougnet (2008)
J. Immunol. 181, 1835-1848
   Abstract »    Full Text »    PDF »
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S. Sehrawat, S. Suvas, P. P. Sarangi, A. Suryawanshi, and B. T. Rouse (2008)
J. Virol. 82, 6838-6851
   Abstract »    Full Text »    PDF »
Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines.
Y. Doi, S. Oki, T. Ozawa, H. Hohjoh, S. Miyake, and T. Yamamura (2008)
PNAS 105, 8381-8386
   Abstract »    Full Text »    PDF »
In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ ROR{gamma}t+ T cells.
M. Lochner, L. Peduto, M. Cherrier, S. Sawa, F. Langa, R. Varona, D. Riethmacher, M. Si-Tahar, J. P. Di Santo, and G. Eberl (2008)
J. Exp. Med. 205, 1381-1393
   Abstract »    Full Text »    PDF »
IL-27R deficiency delays the onset of colitis and protects from helminth-induced pathology in a model of chronic IBD.
A. V. Villarino, D. Artis, J. S. Bezbradica, O. Miller, C. J. M. Saris, S. Joyce, and C. A. Hunter (2008)
Int. Immunol. 20, 739-752
   Abstract »    Full Text »    PDF »
Anti-Inflammatory Effects of FTY720 against Viral-Induced Immunopathology: Role of Drug-Induced Conversion of T Cells to Become Foxp3+ Regulators.
S. Sehrawat and B. T. Rouse (2008)
J. Immunol. 180, 7636-7647
   Abstract »    Full Text »    PDF »
STAT6 Inhibits TGF-{beta}1-mediated Foxp3 Induction through Direct Binding to the Foxp3 Promoter, Which Is Reverted by Retinoic Acid Receptor.
H. Takaki, K. Ichiyama, K. Koga, T. Chinen, G. Takaesu, Y. Sugiyama, S. Kato, A. Yoshimura, and T. Kobayashi (2008)
J. Biol. Chem. 283, 14955-14962
   Abstract »    Full Text »    PDF »
Immunological signaling networks: Integrating the body's immune response.
J. D. Lippolis (2008)
J Anim Sci 86, E53-E63
   Abstract »    Full Text »    PDF »
Th17 cells: a third subset of CD4+ T effector cells involved in organ-specific autoimmunity.
C. Kurts (2008)
Nephrol. Dial. Transplant. 23, 816-819
   Full Text »    PDF »
A CD8+/CD103high T Cell Subset Regulates TNF-Mediated Chronic Murine Ileitis.
J. Ho, C. C. Kurtz, M. Naganuma, P. B. Ernst, F. Cominelli, and J. Rivera-Nieves (2008)
J. Immunol. 180, 2573-2580
   Abstract »    Full Text »    PDF »
Natural Regulatory T Cells and Persistent Viral Infection.
S. Li, E. J. Gowans, C. Chougnet, M. Plebanski, and U. Dittmer (2008)
J. Virol. 82, 21-30
   Full Text »    PDF »
Interleukin-17 Production in Central Nervous System-Infiltrating T Cells and Glial Cells Is Associated with Active Disease in Multiple Sclerosis.
J. S. Tzartos, M. A. Friese, M. J. Craner, J. Palace, J. Newcombe, M. M. Esiri, and L. Fugger (2008)
Am. J. Pathol. 172, 146-155
   Abstract »    Full Text »    PDF »
Dendritic cells are specialized accessory cells along with TGF- for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3 precursors.
S. Yamazaki, A. J. Bonito, R. Spisek, M. Dhodapkar, K. Inaba, and R. M. Steinman (2007)
Blood 110, 4293-4302
   Abstract »    Full Text »    PDF »
Retinoids and T-Cell Balance.
(2007)
Journal Watch Dermatology 2007, 2
   Full Text »
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
   Abstract »    Full Text »    PDF »
Emerging Challenges in Regulatory T Cell Function and Biology.
S. Sakaguchi and F. Powrie (2007)
Science 317, 627-629
   Abstract »    Full Text »    PDF »


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