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

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Item Type:Article
Title:Decitabine inhibits T cell proliferation via a novel TET2-dependent mechanism and exerts potent protective effect in mouse auto- and allo-immunity models
Creators Name:Wang, X. and Wang, J. and Yu, Y. and Ma, T. and Chen, P. and Zhou, B. and Tao, R.
Abstract: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.
Keywords:Decitabine, Experimental Autoimmune Encephalomyelitis, Cardiac Transplantation, T Cell Proliferation, TET2, Animals, Mice
Source:Oncotarget
ISSN:1949-2553
Publisher:Impact Journals (U.S.A.)
Volume:8
Number:34
Page Range:56802-56815
Date:22 August 2017
Official Publication:https://doi.org/10.18632/oncotarget.18063
PubMed:View item in PubMed

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