Research Papers:

Decitabine inhibits T cell proliferation via a novel TET2-dependent mechanism and exerts potent protective effect in mouse auto- and allo-immunity models

Xue Wang, Jun Wang, Yong Yu, Tonghui Ma, Ping Chen, Bing Zhou and Ran Tao _

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Oncotarget. 2017; 8:56802-56815. https://doi.org/10.18632/oncotarget.18063

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Xue Wang1,*, Jun Wang2,*, Yong Yu3, Tonghui Ma4, Ping Chen4,5, Bing Zhou4,6 and Ran Tao4,7

1Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China

2Department of Thoracic Surgery, Hangzhou Municipal Hospital of Traditional Chinese Medicine, Hangzhou, PR China

3Max Delbrück Center for Molecular Medicine, Berlin, Germany

4Provincial Key Laboratory of Cardiac Transplantation, Zhejiang Provincial People’s Hospital (ZJPPH), Hangzhou, PR China

5Department of Obstetrics & Gynecology, Shaoxing Second Municipal Hospital, Shaoxing, PR China

6Department of Cardiothoracic Surgery, Zhejiang Provincial People’s Hospital (ZJPPH), Hangzhou, PR China

7Department of Hepatobiliary-Pancreatic & Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital (ZJPPH), Hangzhou, PR China

*These authors have contributed equally to this work

Correspondence to:

Ran Tao, email: [email protected]

Bing Zhou, email: [email protected]

Keywords: decitabine, experimental autoimmune encephalomyelitis, cardiac transplantation, T cell proliferation, TET2

Received: March 22, 2017    Accepted: April 25, 2017    Published: May 22, 2017


Multiple sclerosis (MS) is an autoimmune disease characterized by the dysregulated immune response including innate and adaptive immune responses. Increasing evidence has proven the importance of epigenetic modification in the progression of MS. Recent studies revealed that low-dose decitabine (Dec, 5-Aza-2’-deoxycytidine), which incorporates into replicating DNA and inhibits DNA methylation, could prevent experimental autoimmune encephalomyelitis (EAE) development by increasing the number of regulatory T cells (Tregs). Here, we showed that higher-dose decitabine relative to previous studies could also distinctly protect mice from EAE and allogeneic cardiac transplantation. Mechanistic studies revealed decitabine suppressed innate responses in EAE mice through inhibiting the activation of microglia and monocyte-derived macrophages that contributed to reduce the severity of EAE. Furthermore, differentiation of naïve CD4+ T cells into Th1 and Th17 cells was significantly suppressed by decitabine in vivo and in vitro. Though in vitro studies showed decitabine could induce Treg differentiation, there was no obvious change in the percentage of Tregs in Dec-treated EAE mice. Most importantly, we found that T cell proliferation was potently inhibited in vivo and in vitro by higher-dose decitabine through increased gene expression of the DNA dioxygenase TET2 which facilitated the expression of several cell cycle inhibitors. Collectively, our study provides novel mechanistic insights of using the epigenetic modifying agents in the management of both allo- and auto-immune responses.

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