| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and
Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115
The de novo generation of Foxp3+ regulatory T (Treg) cells in the peripheral immune compartment and the differentiation of Th17 cells both require TGF-β, and IL-6 and IL-21 are switch factors that drive the development of Th17 cells at the expense of Treg cell generation. The major vitamin A metabolite all-trans retinoic acid (RA) not only enforces the generation of Treg cells but also inhibits the differentiation of Th17 cells. Herein we show that RA enhances TGF-β signaling by increasing the expression and phosphorylation of Smad3, and this results in increased Foxp3 expression even in the presence of IL-6 or IL-21. RA also inhibits the expression of IL-6R
, IRF-4, and IL-23R and thus inhibits Th17 development. In vitro, RA significantly promotes Treg cell conversion, but in vivo during the development of experimental autoimmune encephalomyelitis it does not increase the frequency of Treg cells in the face of an ongoing inflammation. However, RA suppresses the disease very efficiently by inhibiting proinflammatory T cell responses, especially pathogenic Th17 responses. These data not only identify the signaling mechanisms by which RA can affect both Treg cell and Th17 differentiation, but they also highlight that in vivo during an autoimmune reaction, RA suppresses autoimmunity mainly by inhibiting the generation of effector Th17 cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work is supported by research grants from the National Multiple Sclerosis Society (to M.O. and V.K.K.) and the National Institutes of Health (to M.O., B.L., and V.K.K.). S.X. is a recipient of the National Multiple Sclerosis Society Postdoctoral Fellowship. T.K. is supported by the Deutsche Forschungsgemeinschaft. S.L. is supported by the Australian National Health and Medical Research Council. B.L. is a recipient of translational grant from Leukemia and Lymphoma Society of America. V.K.K. is a recipient of the Javits Neuroscience Investigator Award from the National Institutes of Health.
2 S.X. and H.J. share first authorship, T.K. and S.M.L. share second authorship, and B.L. and V.K.K. share senior authorship.
3 Current address: Technical University, Department of Neurology, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 Munich, Germany.
4 Address correspondence and reprint requests to Dr. Vijay K. Kuchroo, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. Email address: vkuchroo{at}rics.bwh.harvard.edu or Dr. Bing Lim, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 77 Avenue Louis Pasteur, Boston, MA, 02115. E-mail address: blim{at}caregroup.harvard.edu
5 Abbreviations used in this paper: Treg, regulatory T; EAE, experimental autoimmune encephalomyelitis; IRF4, IFN regulatory factor 4; iTreg, induced regulatory T; LN, lymph node; MOG, myelin oligodendrocyte glycoprotein; nTreg, natural regulatory T; RA, retinoic acid; RAR, retinoic acid receptor; ROR, retinoic acid-related orphan receptor; RXR, retinoic X receptor; 7-AAD, 7-aminoactinomycin D; Th0, neutral T cell differentiation conditions.
This article has been cited by other articles:
|
|
 |
|
  C. Klemann, B. J.E. Raveney, A. K. Klemann, T. Ozawa, S. von Horsten, K. Shudo, S. Oki, and T. Yamamura Synthetic Retinoid AM80 Inhibits Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis Am. J. Pathol., June 1, 2009; 174(6): 2234 - 2245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Awasthi and V. K. Kuchroo Th17 cells: from precursors to players in inflammation and infection Int. Immunol., May 1, 2009; 21(5): 489 - 498. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
