Abstract
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 Thcell subsets. Although Th1- and Th 2-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 Th 1 and Th2 lineages. Gfi1 expression was enhanced by the IFN-γ/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 γt 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.
| Original language | English |
|---|---|
| Pages (from-to) | 881-889 |
| Number of pages | 9 |
| Journal | International Immunology |
| Volume | 21 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 2009 |
Fingerprint
Keywords
- IL
- Smad
- STAT
- Transcription factor
ASJC Scopus subject areas
- Immunology
Cite this
Gfi1 negatively regulates Th17 differentiation by inhibiting RORγt activity. / Ichiyama, Kenji; Hashimoto, Masayuki; Sekiya, Takashi; Nakagawa, Ryusuke; Wakabayashi, Yu; Sugiyama, Yuki; Komai, Kyoko; Saba, Ingrid; Möröy, Tarik; Yoshimura, Akihiko.
In: International Immunology, Vol. 21, No. 7, 2009, p. 881-889.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Gfi1 negatively regulates Th17 differentiation by inhibiting RORγt activity
AU - Ichiyama, Kenji
AU - Hashimoto, Masayuki
AU - Sekiya, Takashi
AU - Nakagawa, Ryusuke
AU - Wakabayashi, Yu
AU - Sugiyama, Yuki
AU - Komai, Kyoko
AU - Saba, Ingrid
AU - Möröy, Tarik
AU - Yoshimura, Akihiko
PY - 2009
Y1 - 2009
N2 - 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 Thcell subsets. Although Th1- and Th 2-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 Th 1 and Th2 lineages. Gfi1 expression was enhanced by the IFN-γ/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 γt 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.
AB - 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 Thcell subsets. Although Th1- and Th 2-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 Th 1 and Th2 lineages. Gfi1 expression was enhanced by the IFN-γ/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 γt 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.
KW - IL
KW - Smad
KW - STAT
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=67649857192&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67649857192&partnerID=8YFLogxK
U2 - 10.1093/intimm/dxp054
DO - 10.1093/intimm/dxp054
M3 - Article
C2 - 19505891
AN - SCOPUS:67649857192
VL - 21
SP - 881
EP - 889
JO - International Immunology
JF - International Immunology
SN - 0953-8178
IS - 7
ER -