All-trans retinoic acid promotes TGF-β-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus.
All-trans retinoic acid promotes TGF-β-induced Tregs via histone modification but not DNA demethylation on Foxp3 gene locus.
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DOI：
10.1371/journal.pone.0024590
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Zheng SG
中科院分区：
文献类型：
--
作者：
Lu L;Ma J;Li Z;Lan Q;Chen M;Liu Y;Xia Z;Wang J;Han Y;Shi W;Quesniaux V;Ryffel B;Brand D;Li B;Liu Z;Zheng SG
全反式维甲酸（all-transretinoic acid，atRA）可促进TGF-β诱导的CD 4 + Foxp 3+调节性T细胞（regulatory T cells，iTreg）的形成，在预防自身免疫反应中发挥重要作用，但其分子机制尚不清楚。因此，我们的目标是确定atRA如何促进iTdR的分化。在TGF-β存在的情况下，将atRA添加到用抗CD 3/CD 28抗体刺激的幼稚CD 4 + CD 25 −细胞中，不仅增加了Foxp 3 + iTreg分化，而且通过凋亡抑制维持了Foxp 3表达。atRA/TGF-β处理的CD 4+细胞发展为完全无反应性并显示出增加的抑制活性。输注atRA/TGF-β处理的CD 4+细胞比单独用TGF-β处理的CD 4+细胞对具有典型狼疮样综合征的慢性GVHD小鼠的症状抑制和存活保护作用更大。atRA没有显著影响Smad 2/3的磷酸化水平，并且仍然促进从Smad 3 KO和Smad 2条件性KO小鼠分离的CD 4+细胞中的iTreg分化。相反，atRA显着增加ERK 1/2激活，和ERK 1/2信号的阻断完全取消了atRA对Foxp 3表达的增强作用。此外，atRA显着增加组蛋白甲基化和乙酰化的启动子和保守的非编码DNA序列（CNS）元件在Foxp 3基因位点和磷-RNA聚合酶II的招聘，而DNA甲基化在CNS 3没有显着改变。我们已经确定了atRA促进iTHBe发展和维持的细胞和分子机制。这些结果将有助于提高iTHBE发展的数量和质量，并可能为自身免疫性疾病患者和需要器官移植的患者的临床细胞治疗提供新的见解。
It has been documented all-trans retinoic acid (atRA) promotes the development of TGF-β-induced CD4+Foxp3+ regulatory T cells (iTreg) that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs. Addition of atRA to naïve CD4+CD25− cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3+ iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-β-treated CD4+ cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-β-treated CD4+ cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4+ cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4+ cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS) elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered. We have identified the cellular and molecular mechanism(s) by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation.
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影响因子：
3.6
作者：
Jinnin, M;Ihn, H;Tamaki, K
通讯作者：
Tamaki, K
DOI：
10.1073/pnas.0700298104
发表时间：
2007-03-13
影响因子：
11.1
作者：
Li, Bin;Samanta, Arabinda;Greene, Mark I.
通讯作者：
Greene, Mark I.
DOI：
10.1084/jem.155.5.1501
发表时间：
1982-05-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Rolink AG;Radaszkiewicz T;Pals ST;van der Meer WG;Gleichmann E
通讯作者：
Gleichmann E
影响因子：
5.4
作者：
Schambach, Felix;Schupp, Michael;Reiner, Steven L.
通讯作者：
Reiner, Steven L.
影响因子：
32.4
作者：
Hill JA;Hall JA;Sun CM;Cai Q;Ghyselinck N;Chambon P;Belkaid Y;Mathis D;Benoist C
通讯作者：
Benoist C