Histone methylation mediates plasticity of human FOXP3+ regulatory T cells by modulating signature gene expressions
Histone methylation mediates plasticity of human FOXP3+ regulatory T cells by modulating signature gene expressions
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组蛋白甲基化通过调节特征基因表达介导人 FOXP3 调节性 T 细胞的可塑性
DOI：
10.1111/imm.12198
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发表时间：
2014-03-01
期刊：
影响因子：
6.4
通讯作者：
Zhang, Yong
中科院分区：
文献类型：
--
作者：
He, Haiqi;Ni, Bing;Zhang, Yong
CD4(+)FOXP3（+）调节性T （Treg）细胞构成异质性和可塑性的T细胞谱系，在维持免疫稳态和免疫耐受中起关键作用。然而，人类Treg细胞在FOXP3表达缺失后的命运以及促成这种表型转换的表观遗传机制仍有待充分阐明。在目前的研究中，我们证明了人类CD4(+)CD25（高）CD127（低/-）Treg细胞在体外抗cd3 /CD28和白细胞介素-2培养后转化为两个具有独特FOXP3（+）和FOXP3（-）表型的亚群。数字基因表达分析显示，体外扩增后，人Treg细胞下调Treg细胞特征基因FOXP3、CTLA4、ICOS、IKZF2、LRRC32等，上调辅助性T谱系相关基因GATA3、GFI1、IL13等，尤其是辅助性T型2 （Th2）相关基因。随后对这些亚群进行染色质免疫沉淀测序，获得了H3K4me3和H3K27me3基因图谱的全基因组图谱。令人惊讶的是，Treg细胞的重编程与不同的组蛋白修饰有关，如在下调的Treg细胞特征基因（如FOXP3、CTLA4和LRRC32位点）中允许的H3K4me3丰度降低，而在th2相关基因（如IL4和IL5）中H3K4me3丰度增加；然而，H3K27me3修饰谱在两个亚群之间没有显著差异。总之，本研究表明，在体外扩增过程中，人Treg细胞FOXP3表达的缺失可以诱导重编程为T辅助细胞表型，其基因表达特征以Th2谱系相关基因为主，并且这种细胞类型转换可能是由组蛋白甲基化事件介导的。
CD4(+)FOXP3(+) regulatory T (Treg) cells constitute a heterogeneous and plastic T-cell lineage that plays a pivotal role in maintaining immune homeostasis and immune tolerance. However, the fate of human Treg cells after loss of FOXP3 expression and the epigenetic mechanisms contributing to such a phenotype switch remain to be fully elucidated. In the current study, we demonstrate that human CD4(+)CD25(high)CD127(low/-) Treg cells convert to two subpopulations with distinctive FOXP3(+) and FOXP3(-) phenotypes following in vitro culture with anti-CD3/CD28 and interleukin-2. Digital gene expression analysis showed that upon in vitro expansion, human Treg cells down-regulated Treg cell signature genes, such as FOXP3, CTLA4, ICOS, IKZF2 and LRRC32, but up-regulated a set of T helper lineage-associated genes, especially T helper type 2 (Th2)-associated, such as GATA3, GFI1 and IL13. Subsequent chromatin immunoprecipitation-sequencing of these subpopulations yielded genome-wide maps of their H3K4me3 and H3K27me3 profiles. Surprisingly, reprogramming of Treg cells was associated with differential histone modifications, as evidenced by decreased abundance of permissive H3K4me3 within the down-regulated Treg cell signature genes, such as FOXP3, CTLA4 and LRRC32 loci, and increased abundance of H3K4me3 within the Th2-associated genes, such as IL4 and IL5; however, the H3K27me3 modification profile was not significantly different between the two subpopulations. In conclusion, this study revealed that loss of FOXP3 expression from human Treg cells during in vitro expansion can induce reprogramming to a T helper cell phenotype with a gene expression signature dominated by Th2 lineage-associated genes, and that this cell type conversion may be mediated by histone methylation events.