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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1013-1020.
Prepublished online as a Blood First Edition Paper on October 19, 2007; DOI 10.1182/blood-2007-06-096438.
 Previous Article | Table of Contents | Next Article 
CHEMOKINES, CYTOKINES, AND INTERLEUKINS
Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway
Kevin M. Elias1,2,
Arian Laurence2,
Todd S. Davidson3,
Geoffrey Stephens3,
Yuka Kanno2,
Ethan M. Shevach3, and
John J. O'Shea2
1 Howard Hughes Medical Institute National Institutes of Health Research Scholars Program, Bethesda, MD;
2 Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD;
3 Laboratory of Immunology, Cellular Immunology Section, National Institute of Allergy and Infectious Disease, Bethesda, MD
CD4+ helper T (Th) cells play a crucial role in the delicate balance between host defense and autoimmune disease. Two important populations of helper T cells are the proinflammatory, interleukin-17 (IL-17)–producing (Th17) cells and the anti-inflammatory forkhead box P3–positive (FoxP3+) T regulatory (Treg) cells. Here we show that all-trans retinoic acid (ATRA) and other agonists of the retinoic acid receptor alpha (RAR ) inhibit the formation of Th17 cells and promote FoxP3 expression. Conversely, inhibition of retinoic acid signaling constrains transforming growth factor beta (TGF-β1) induction of FoxP3. The effect of ATRA is mediated independently of IL-2, signal transducer and activator of transcription 5 (Stat5) and Stat3, representing a novel mechanism for the induction of FoxP3 in CD4 T cells. As previous studies have shown that vitamin A derivatives are protective in animal models of autoimmune disease, the current data suggest a previously unrecognized role for RAR in the regulation of CD4+ T-cell differentiation and provide a mechanism for the anti-inflammatory effects of retinoic acid.
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