Coordinated Changes in DNA Methylation in Antigen-Specific Memory CD4 T Cells
Coordinated Changes in DNA Methylation in Antigen-Specific Memory CD4 T Cells
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DOI：
10.4049/jimmunol.1202267
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发表时间：
2013-04-15
影响因子：
4.4
通讯作者：
Matsushima, Kouji
中科院分区：
文献类型：
--
作者：
Hashimoto, Shin-ichi;Ogoshi, Katsumi;Matsushima, Kouji
记忆性CD4(+)T细胞是体液免疫和细胞免疫反应的中枢调节细胞。T细胞分化导致细胞因子基因染色质结构和DNA甲基化的特异性变化。虽然已经检测了T细胞中有限数量的基因位点的甲基化状态，但记忆性CD4(+)T细胞的全基因组DNA甲基化状态仍未被探索。为了进一步阐明记忆T细胞的分子特征，我们对来自TCR转基因小鼠的T细胞产生的记忆CD4(+)T细胞进行了甲基组和转录组分析。由此产生的全基因组DNA甲基化图谱显示，在T细胞分化过程中，小鼠基因组中有1144个差异甲基化区域(DMRS)，其中552个与基因位点相关。有趣的是，这些DMR大多位于内含子中。这些DMRS包括CXCR6、Tbox21、Chsy1和CISH等基因，这些基因与细胞因子的产生、骨髓归巢和免疫反应相关。暴露在特定抗原下的记忆T细胞的甲基化变化似乎调节了免疫相关基因的增强子活性，而不是启动子活性。此外，记忆T细胞亚群之间的甲基化特征不同，表明T细胞甲基化状态和T细胞分化之间存在联系。通过比较初始记忆T细胞和抗原特异性记忆T细胞的DMR，本研究为记忆T细胞的功能状态提供了新的见解。免疫学杂志，2013,190：4076-4091。
Memory CD4(+) T cells are central regulators of both humoral and cellular immune responses. T cell differentiation results in specific changes in chromatin structure and DNA methylation of cytokine genes. Although the methylation status of a limited number of gene loci in T cells has been examined, the genome-wide DNA methylation status of memory CD4(+) T cells remains unexplored. To further elucidate the molecular signature of memory T cells, we conducted methylome and transcriptome analyses of memory CD4(+) T cells generated using T cells from TCR-transgenic mice. The resulting genome-wide DNA methylation profile revealed 1144 differentially methylated regions (DMRs) across the murine genome during the process of T cell differentiation, 552 of which were associated with gene loci. Interestingly, the majority of these DMRs were located in introns. These DMRs included genes such as CXCR6, Tbox21, Chsy1, and Cish, which are associated with cytokine production, homing to bone marrow, and immune responses. Methylation changes in memory T cells exposed to specific Ag appeared to regulate enhancer activity rather than promoter activity of immunologically relevant genes. In addition, methylation profiles differed between memory T cell subsets, demonstrating a link between T cell methylation status and T cell differentiation. By comparing DMRs between naive and Ag-specific memory T cells, this study provides new insights into the functional status of memory T cells. The Journal of Immunology, 2013, 190: 4076-4091.