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International Immunology Advance Access originally published online on April 20, 2009
International Immunology 2009 21(6):679-689; doi:10.1093/intimm/dxp037
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© The Japanese Society for Immunology. 2009. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Protein geranylgeranylation regulates the balance between Th17 cells and Foxp3+ regulatory T cells

Shin-ichiro Kagami1,2, Takayoshi Owada2,*, Hiroko Kanari1,*, Yukari Saito2, Akira Suto1,2, Kei Ikeda2, Koichi Hirose2, Norihiko Watanabe2, Itsuo Iwamoto3 and Hiroshi Nakajima1,2

1 Department of Molecular Genetics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chiba City, Chiba 260-8670, Japan
2 Department of Allergy and Clinical Immunology, Chiba University Hospital, Chiba, Japan
3 Research Center for Allergy and Clinical Immunology, Asahi General Hospital, Chiba, Japan

Correspondence to: H. Nakajima; E-mail: nakajimh{at}faculty.chiba-u.jp

Recent studies have suggested that statins, the inhibitors for 3-hydroxy-3-methyglutaryl (HMG)-CoA reductase in the mevalonate pathway, exhibit anti-inflammatory effects. However, the immune modulatory effects of statins on the differentiation of CD4+ T cells and their underlying mechanisms are still largely unknown. To address these issues, we examined the effect of simvastatin and inhibitors for protein farnesylation and geranylgeranylation on the differentiation of IL-17-producing T cells (Th17 cells) and Foxp3+ CD4+ T cells. Simvastatin inhibited the differentiation of Th17 cells through the inhibition of HMG-CoA reductase activity but enhanced the differentiation of Foxp3+ CD4+ T cells. Geranylgeranyltransferase I inhibitor, GGTI-298, but not farnesyltransferase inhibitor, FTI-277, mimicked the effects of simvastatin, indicating that the inhibition of protein geranylgeranylation is responsible for the effects. Moreover, Foxp3+ CD4+ T cells developed in the presence of transforming growth factor-β and GGTI-298 functioned as regulatory T cells (Tregs) in in vitro T cell proliferation assay as well as in an autoimmune colitis model. Finally, GGTI-298 induced SOCS3 expression and inhibited IL-6-induced signal transducers and activators of transcription3 phosphorylation in CD4+ T cells. Taken together, these results indicate that protein geranylgeranylation enhances the differentiation of Th17 cells and inhibits the differentiation of Foxp3+ Tregs partly via the inhibition of SOCS3 expression.

Keywords: SOCS3, statin, T cells, tolerance

* These authors contributed equally to this study.

Transmitting editor: Karasuyama

Received 4 November 2008, accepted 24 March 2009.


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