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Science 317 (5835): 256-260

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

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*

Abstract: 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}

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Oral Administration of Retinoic Acid Receptor-{alpha}/{beta}-Specific Ligand Am80 Suppresses Experimental Autoimmune Uveoretinitis.
H. Keino, T. Watanabe, Y. Sato, and A. A. Okada (2011)
Invest. Ophthalmol. Vis. Sci. 52, 1548-1556
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Host APCs Augment In Vivo Expansion of Donor Natural Regulatory T Cells via B7H1/B7.1 in Allogeneic Recipients.
T. Yi, X. Li, S. Yao, L. Wang, Y. Chen, D. Zhao, H. F. Johnston, J. S. Young, H. Liu, I. Todorov, et al. (2011)
J. Immunol. 186, 2739-2749
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Expression of Retinaldehyde Dehydrogenase Enzymes in Mucosal Dendritic Cells and Gut-Draining Lymph Node Stromal Cells Is Controlled by Dietary Vitamin A.
R. Molenaar, M. Knippenberg, G. Goverse, B. J. Olivier, A. F. de Vos, T. O'Toole, and R. E. Mebius (2011)
J. Immunol. 186, 1934-1942
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Retinoic Acid-Induced CCR9 Expression Requires Transient TCR Stimulation and Cooperativity between NFATc2 and the Retinoic Acid Receptor/Retinoid X Receptor Complex.
Y. Ohoka, A. Yokota, H. Takeuchi, N. Maeda, and M. Iwata (2011)
J. Immunol. 186, 733-744
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Naive and activated T cells display differential responsiveness to TL1A that affects Th17 generation, maintenance, and proliferation.
G. W. Jones, J. S. Stumhofer, T. Foster, J. P. Twohig, P. Hertzog, N. Topley, A. S. Williams, C. A. Hunter, B. J. Jenkins, E. C. Y. Wang, et al. (2011)
FASEB J 25, 409-419
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