Human Th1 and Th17 Cells Exhibit Epigenetic Stability at Signature Cytokine and Transcription Factor Loci
Human Th1 and Th17 Cells Exhibit Epigenetic Stability at Signature Cytokine and Transcription Factor Loci
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DOI：
10.4049/jimmunol.1101058
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发表时间：
2011-12-01
影响因子：
4.4
通讯作者：
Levings, Megan K.
中科院分区：
文献类型：
--
作者：
Cohen, Carla J.;Crome, Sarah Q.;Levings, Megan K.
Th细胞谱系定型的线性模型由于成熟Th细胞可以转分化成交替谱系的报道而被修正。Th细胞的这种重编程能力被认为是由表观遗传机制调节的，表观遗传机制控制相反谱系的转录因子特征的表达。然而，目前还不清楚这种Th细胞可塑性的新模型在何种程度上适用于在体内生理条件下发育的人Th细胞亚群。我们分离了体内分化的人Th 1和Th 17细胞，以及中间Th 1/17细胞，并在细胞因子（IFNG和IL 17 A）和转录因子（TBX 21，RORC和RORA）基因座上鉴定了不同的表观遗传特征。我们还检查了暴露于Th 1极化条件下的人Th 17细胞的表型和表观遗传稳定性，发现尽管它们可以上调TBX 21和IFN-γ，但这在没有IL-17或RORC表达损失的情况下发生，并导致具有Th 1/17表型的细胞。类似地，Th 1细胞可以在RORC 2的强制表达后上调IL-17，但不丧失IFN-γ或TBX 21的表达。尽管这些特征基因的表达发生了变化，但除了在细胞因子基因启动子处获得活性组蛋白甲基化标记外，表观遗传修饰非常稳定。人Th 17和Th 1细胞进行完全谱系转换的有限能力表明双能Th 1/17细胞可能来自Th 1和/或Th 17细胞。这些数据还质疑Th细胞谱系可塑性的新模型对体内极化的人Th细胞亚群的广泛适用性。免疫学杂志，2011，187：5615-5626。
The linear model of Th cell lineage commitment is being revised due to reports that mature Th cells can trans-differentiate into alternate lineages. This ability of Th cells to reprogram is thought to be regulated by epigenetic mechanisms that control expression of transcription factors characteristic of opposing lineages. It is unclear, however, to what extent this new model of Th cell plasticity holds true in human Th cell subsets that develop under physiological conditions in vivo. We isolated in vivo-differentiated human Th1 and Th17 cells, as well as intermediate Th1/17 cells, and identified distinct epigenetic signatures at cytokine (IFNG and IL17A) and transcription factor (TBX21, RORC, and RORA) loci. We also examined the phenotypic and epigenetic stability of human Th17 cells exposed to Th1-polarizing conditions and found that although they could upregulate TBX21 and IFN-gamma, this occurred without loss of IL-17 or RORC expression, and resulted in cells with a Th1/17 phenotype. Similarly, Th1 cells could upregulate IL-17 upon enforced expression of RORC2, but did not lose expression of IFN-gamma or TBX21. Despite alterations in expression of these signature genes, epigenetic modifications were remarkably stable aside from the acquisition of active histone methylation marks at cytokine gene promoters. The limited capacity of human Th17 and Th1 cells to undergo complete lineage conversion suggests that the bipotent Th1/17 cells may arise from Th1 and/or Th17 cells. These data also question the broad applicability of the new model of Th cell lineage plasticity to in vivo-polarized human Th cell subsets. The Journal of Immunology, 2011, 187: 5615-5626.