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International Immunology Advance Access originally published online on June 7, 2009
International Immunology 2009 21(7):881-889; doi:10.1093/intimm/dxp054
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© The Japanese Society for Immunology. 2009. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Gfi1 negatively regulates Th17 differentiation by inhibiting ROR{gamma}t activity

Kenji Ichiyama1, Masayuki Hashimoto1, Takashi Sekiya1, Ryusuke Nakagawa1, Yu Wakabayashi1,3, Yuki Sugiyama1,3, Kyoko Komai1, Ingrid Saba2, Tarik Möröy2 and Akihiko Yoshimura1,3

1 Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
2 Institut de recherches cliniques de Montréal, Departement de Microbiologie et Immunologie, Université de Montréal, 110 Avenue des Pins West Montréal, Quebec H2W 1R7, Canada
3 Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo 102-0075, Japan

Correspondence to: A. Yoshimura; E-mail: yakihiko{at}a6.keio.jp

Th cells have long been divided into two subsets, Th1 and Th2; however, recently, Th17 and inducible regulatory T (iTreg) cells were identified as new Th cell subsets. Although Th1- and Th2-polarizing cytokines have been shown to suppress Th17 and iTreg development, transcriptional regulation of Th17 and iTreg differentiation by cytokines remains to be clarified. In this study, we found that expression of the growth factor independent 1 (Gfi1) gene, which has been implicated in Th2 development, was repressed in Th17 and iTreg cells compared with Th1 and Th2 lineages. Gfi1 expression was enhanced by the IFN-{gamma}/STAT1 and IL-4/STAT6 pathways, whereas it was repressed by the transforming growth factor-β1 stimulation at the promoter level. Over-expression of Gfi1 strongly reduced IL-17A transcription in the EL4 T cell line, as well as in primary T cells. This was due to the blockade of recruitment of retinoid-related orphan receptor {gamma}t to the IL-17A promoter. In contrast, IL-17A expression was significantly enhanced in Gfi1-deficient T cells under Th17-promoting differentiation conditions as compared with wild-type T cells. In contrast, the impacts of Gfi1 in iTregs were not as strong as in Th17 cells. Taken together, these data strongly suggest that Gfi1 is a negative regulator of Th17 differentiation, which represents a novel mechanism for the regulation of Th17 development by cytokines.

Keywords: IL, Smad, STAT, transcription factor

Transmitting editor: T. Watanabe

Received 29 January 2009, accepted 13 May 2009.


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