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J. Biol. Chem., Vol. 283, Issue 25, 17003-17008, June 20, 2008

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Foxp3 Inhibits RORt-mediated IL-17A mRNA Transcription through Direct Interaction with RORt^*

Kenji Ichiyama, Hideyuki Yoshida, Yu Wakabayashi, Takatoshi Chinen, Kazuko Saeki, Mako Nakaya, Giichi Takaesu, Shohei Hori^¶, Akihiko Yoshimura¹, and Takashi Kobayashi²

From the Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, the Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, and the ^¶Research Unit for Immune Homeostasis, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan

The cytokine, transforming growth factor-β1 (TGF-β1), converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of interleukin (IL)-6, TGF-β1 has also been found to promote differentiation into IL-17-producing helper T (Th17) cells that are deeply involved in autoimmunity and inflammation. However, it has not been clarified how TGF-β1 and IL-6 determine such a distinct fate. Here we found that a master regulator for Th17, retinoic acid-related orphan receptor t (RORt), was rapidly induced by TGF-β1 regardless of the presence of IL-6. IL-6 reduced Foxp3 expression, and overexpression of Foxp3 in a T cell line resulted in a strong reduction of IL-17A expression. We have characterized the IL-17A promoter and found that RORt binding is sufficient for activation of the minimum promoter in the HEK 293T cells. RORt-mediated IL-17A promoter activation was suppressed by forced expression of Foxp3. Foxp3 directly interacted with RORt through exon 2 region of Foxp3. The exon 2 region and forkhead (FKH) domain of Foxp3 were necessary for the suppression of RORt-mediated IL-17A promoter activation. We propose that induction of Foxp3 is the mechanism for the suppression of Th17 and polarization into inducible Treg.

Received for publication, February 19, 2008 , and in revised form, April 11, 2008.

^* This work was supported by special grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO), the Takeda Science Foundation, the Naito Foundation, the Nakatomi Foundation, the Yakult Bioscience Foundation, the Japan Intractable Disease Research Foundation, the Mitsubishi Pharma Research Foundation, the Uehara Memorial Foundation, the Suzuken Memorial Foundation, and the Princess Takamatsu Cancer Research Fund. 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.

This article was selected as a Paper of the Week.

¹ To whom correspondence may be addressed. Tel.: 81-92-642-6822; Fax: 81-92-642-6825; E-mail: yoshimura{at}a6.keio.jp. ² To whom correspondence may be addressed. Tel.: 81-92-642-6822; Fax: 81-92-642-6825; E-mail: takashik{at}bioreg.kyushu-u.ac.jp.

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