Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8(+) T cells sensitizing them to apoptotic cell death.
Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8(+) T cells sensitizing them to apoptotic cell death.
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DOI：
10.1111/j.1474-9726.2012.00819.x
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发表时间：
2012-08
期刊：
影响因子：
7.8
通讯作者：
Grubeck-Loebenstein B
中科院分区：
文献类型：
--
作者：
Brunner S;Herndler-Brandstetter D;Arnold CR;Wiegers GJ;Villunger A;Hackl M;Grillari J;Moreno-Villanueva M;Bürkle A;Grubeck-Loebenstein B
记忆性CD8 + T细胞的终身内稳态以及持续性病毒感染已被证明会促进高度分化的CD8 + CD28 - T细胞的积累，这种现象与人类免疫功能受损有关。然而，调节CD8 + CD28 - T细胞内稳态的分子机制尚未阐明。在这项研究中，我们证明在人类胸腺后CD8 + T细胞分化过程中，miR - 23～24～27簇会上调。CD8 + CD28 - T细胞中miR - 24表达的增加与组蛋白变体H2AX表达的降低有关，H2AX是一种在DNA损伤反应（DDR）中起关键作用的蛋白质。用经典化疗药物依托泊苷（一种拓扑异构酶II抑制剂）处理后，与CD8 + CD28 + T细胞相比，CD8 + CD28 - T细胞的凋亡增加，并且与这种细胞类型中受损的DDR相关。通过DNA解旋自动荧光分析（FADU）试验以及H2AX在Ser139、ATM在Ser1981和p53在Ser15的磷酸化降低，表明CD8 + CD28 - T细胞修复DNA的能力降低。白细胞介素（IL）- 15能够阻止依托泊苷介导的CD8 + CD28 - T细胞凋亡，这表明IL - 15在人类CD8 + CD28 - T细胞的存活以及年龄相关的积累中起作用。
The life-long homeostasis of memory CD8+ T cells as well as persistent viral infections have been shown to facilitate the accumulation of highly differentiated CD8+CD28− T cells, a phenomenon that has been associated with an impaired immune function in humans. However, the molecular mechanisms regulating homeostasis of CD8+CD28− T cells have not yet been elucidated. In this study, we demonstrate that the miR-23∼24∼27 cluster is up-regulated during post-thymic CD8+ T-cell differentiation in humans. The increased expression of miR-24 in CD8+CD28− T cells is associated with decreased expression of the histone variant H2AX, a protein that plays a key role in the DNA damage response (DDR). Following treatment with the classic chemotherapeutic agent etoposide, a topoisomerase II inhibitor, apoptosis was increased in CD8+CD28− when compared to CD8+CD28+ T cells and correlated with an impaired DDR in this cell type. The reduced capacity of CD8+CD28− T cell to repair DNA was characterized by the automated fluorimetric analysis of DNA unwinding (FADU) assay as well as by decreased phosphorylation of H2AX at Ser139, of ATM at Ser1981, and of p53 at Ser15. Interleukin (IL)-15 could prevent etoposide-mediated apoptosis of CD8+CD28− T cells, suggesting a role for IL-15 in the survival and the age-dependent accumulation of CD8+CD28− T cells in humans.
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影响因子：
4.5
作者：
Grillari, Johannes;Hackl, Matthias;Grillari-Voglauer, Regina
通讯作者：
Grillari-Voglauer, Regina
影响因子：
7.8
作者：
Alonso-Arias, Rebeca;Moro-Garcia, Marco A.;Lopez-Larrea, Carlos
通讯作者：
Lopez-Larrea, Carlos
DOI：
10.1073/pnas.1016045108
发表时间：
2011-05-17
影响因子：
11.1
作者：
Asaithamby, Aroumougame;Hu, Burong;Chen, David J.
通讯作者：
Chen, David J.
影响因子：
5.3
作者：
Saule, P;Trauet, J;Labalette, M
通讯作者：
Labalette, M
影响因子：
2.6
作者：
Pawelec, G;Koch, S;Wikby, A
通讯作者：
Wikby, A