Epigenetic control of the foxp3 locus in regulatory T cells.
Epigenetic control of the foxp3 locus in regulatory T cells.
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DOI：
10.1371/journal.pbio.0050038
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发表时间：
2007-02
期刊：
影响因子：
9.8
通讯作者：
Huehn J
中科院分区：
文献类型：
--
作者：
Floess S;Freyer J;Siewert C;Baron U;Olek S;Polansky J;Schlawe K;Chang HD;Bopp T;Schmitt E;Klein-Hessling S;Serfling E;Hamann A;Huehn J
令人信服的证据表明，转录因子Foxp 3作为一个主开关控制CD 4+调节性T细胞（T细胞）的发展和功能。然而，Foxp 3表达的转录控制本身是否有助于稳定Treg谱系的发育迄今尚未研究。我们在这里确定了一个进化保守的区域内的foxp 3基因座上游外显子1具有转录活性。亚硫酸氢盐测序和染色质免疫沉淀显示，在离体分离的Foxp 3 + CD 25 + CD 4 + T细胞中，CpG基序完全去甲基化以及保守区域内的组蛋白修饰，但在幼稚的CD 25 − CD 4 + T细胞中没有。在发育中的Foxp 3+胸腺细胞中已经发现了部分DNA去甲基化;然而，尽管Foxp 3表达高，但TGF-β体外诱导的THBG仅显示不完全的去甲基化。与天然T细胞相比，这些TGF-β诱导的Foxp 3 + T细胞在不存在TGF-β的情况下在再刺激时失去Foxp 3表达和抑制活性。我们的数据表明，Foxp 3的表达必须通过表观遗传修饰来稳定，以允许永久性抑制细胞谱系的发展，这一发现对于涉及诱导或转移THBG的治疗应用以及对于理解长期细胞谱系决定具有重要意义。调节性T细胞通过防止自身免疫或过度激活对病原体应答的T细胞（幼稚T细胞和效应T细胞），在维持免疫系统内的自身耐受性方面发挥关键作用。它们在胸腺内分化，但也可以在身体其他部位重新诱导。决定稳定调节性T细胞谱系发展的机制尚不清楚。我们的研究为表观遗传修饰在编码叉头转录因子Foxp 3的基因座中的关键作用提供了证据，Foxp 3作为控制调节性T细胞发育和功能的主开关：该基因的非编码部分内的进化保守区域包含CpG基序，其在调节性T细胞中完全去甲基化，但在幼稚和效应T细胞中甲基化，而我们观察到乙酰化组蛋白的反向发生，这是另一种表观遗传染色质修饰。体外诱导的调节性T细胞-与天然调节性T细胞相反，不显示稳定的调节性T细胞表型-尽管Foxp 3表达高，但仅显示不完全的DNA去甲基化。我们的数据表明，Foxp 3的表达必须通过表观遗传修饰来稳定，以产生永久的抑制细胞谱系，这一发现对于涉及诱导或转移调节性T细胞的治疗应用以及理解长期细胞谱系决定具有重要意义。转录因子Foxp 3是调节性T细胞谱系的主开关。作者表明，Foxp 3基因座在稳定的调节性T细胞中被表观遗传修饰。
Compelling evidence suggests that the transcription factor Foxp3 acts as a master switch governing the development and function of CD4+ regulatory T cells (Tregs). However, whether transcriptional control of Foxp3 expression itself contributes to the development of a stable Treg lineage has thus far not been investigated. We here identified an evolutionarily conserved region within the foxp3 locus upstream of exon-1 possessing transcriptional activity. Bisulphite sequencing and chromatin immunoprecipitation revealed complete demethylation of CpG motifs as well as histone modifications within the conserved region in ex vivo isolated Foxp3+CD25+CD4+ Tregs, but not in naïve CD25−CD4+ T cells. Partial DNA demethylation is already found within developing Foxp3+ thymocytes; however, Tregs induced by TGF-β in vitro display only incomplete demethylation despite high Foxp3 expression. In contrast to natural Tregs, these TGF-β–induced Foxp3+ Tregs lose both Foxp3 expression and suppressive activity upon restimulation in the absence of TGF-β. Our data suggest that expression of Foxp3 must be stabilized by epigenetic modification to allow the development of a permanent suppressor cell lineage, a finding of significant importance for therapeutic applications involving induction or transfer of Tregs and for the understanding of long-term cell lineage decisions. Regulatory T cells play a pivotal role in the maintenance of self-tolerance within the immune system by preventing autoimmunity or excessive activation of the T cells that respond to pathogens (naïve and effector T cells). They differentiate within the thymus, but can also be de novo induced in the rest of the body. Mechanisms determining development of a stable regulatory T cell lineage are unknown. Our study provides evidence for a critical role of epigenetic modifications in the locus coding for the forkhead transcription factor Foxp3, which acts as a master switch controlling regulatory T cell development and function: An evolutionarily conserved region within the non-coding part of the gene contains CpG motifs, which are completely demethylated in regulatory T cells, but methylated in naïve and effector T cells, whereas we observed an inverse occurrence of acetylated histones, another epigenetic chromatin modification. Regulatory T cells induced in vitro—which, in contrast to natural regulatory T cells, do not display a stable regulatory T cell phenotype—display only incomplete DNA demethylation despite high Foxp3 expression. Our data suggest that expression of Foxp3 must be stabilized by epigenetic modification to result in a permanent suppressor cell lineage, a finding of significant importance for therapeutic applications involving induction or transfer of regulatory T cells and for the understanding of long-term cell lineage decisions. The transcription factor Foxp3 is a master switch for the regulatory T cell lineage. The authors show that the Foxp3 locus is epigenetically modified in stable regulatory T cells.
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影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
15.3
作者：
Apostolou, I;von Boehmer, H
通讯作者：
von Boehmer, H
影响因子：
24.5
作者：
Fantini, MC;Becker, C;Neurath, MF
通讯作者：
Neurath, MF
发育阶段、表型和迁移可区分幼稚型和效应/记忆型 CD4+ 调节性 T 细胞。
DOI：
10.1084/jem.20031562
发表时间：
2004-02-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Huehn J;Siegmund K;Lehmann JC;Siewert C;Haubold U;Feuerer M;Debes GF;Lauber J;Frey O;Przybylski GK;Niesner U;de la Rosa M;Schmidt CA;Bräuer R;Buer J;Scheffold A;Hamann A
通讯作者：
Hamann A
影响因子：
56.9
作者：
Hori, S;Nomura, T;Sakaguchi, S
通讯作者：
Sakaguchi, S