Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming.
Phenotypic alteration of CD8+ T cells in chronic lymphocytic leukemia is associated with epigenetic reprogramming.
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DOI：
10.18632/oncotarget.9941
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Shi H
中科院分区：
文献类型：
--
作者：
Wu J;Xu X;Lee EJ;Shull AY;Pei L;Awan F;Wang X;Choi JH;Deng L;Xin HB;Zhong W;Liang J;Miao Y;Wu Y;Fan L;Li J;Xu W;Shi H
免疫抑制是慢性淋巴细胞白血病(CLL)患者的普遍临床特征，许多患者表现出对感染的易感性增加以及抗肿瘤免疫反应失败的增加。然而，目前关于CLL中这种免疫抑制表型的确切机制尚不清楚。为了进一步阐明这一特殊现象，我们分析了大量队列中CLL患者样本的T细胞分布，观察到CD4/CD8比率倒置的患者首次治疗的时间更短，总体存活率也更低。与年龄匹配的健康供者相比，CLL患者CD8+T细胞中免疫检查点受体PD-1的表达水平较高。有趣的是，我们发现CD8+T细胞中PD-1表达的增加与PD-1基因PDCD1远端上游位点DNA甲基化水平的降低相对应。使用荧光素酶报告分析进一步的分析表明，识别的PDCD1远端上游区域作为PDCD1转录的增强子，并且在抗CD3/抗CD28抗体和IL2激活幼稚CD8+T细胞的过程中，该区域被去甲基化。最后，我们进行了全基因组DNA甲基化分析，比较了CLL患者和健康捐赠者的CD8+T细胞，并确定了其他具有已知免疫调节功能的差异甲基化基因，包括CCR6和KLRG1。综上所述，我们的发现揭示了CLL患者CD8+T细胞内发生的表观遗传重编程，并突出了CLL如何实现免疫抑制的潜在机制。
Immunosuppression is a prevalent clinical feature in chronic lymphocytic leukemia (CLL) patients, with many patients demonstrating increased susceptibility to infections as well as increased failure of an antitumor immune response. However, much is currently not understood regarding the precise mechanisms that attribute to this immunosuppressive phenotype in CLL. To provide further clarity to this particular phenomenon, we analyzed the T-cell profile of CLL patient samples within a large cohort and observed that patients with an inverted CD4/CD8 ratio had a shorter time to first treatment as well as overall survival. These observations coincided with higher expression of the immune checkpoint receptor PD-1 in CLL patient CD8+ T cells when compared to age-matched healthy donors. Interestingly, we discovered that increased PD-1 expression in CD8+ T cells corresponds with decreased DNA methylation levels in a distal upstream locus of the PD-1 gene PDCD1. Further analysis using luciferase reporter assays suggests that the identified PDCD1 distal upstream region acts as an enhancer for PDCD1 transcription and this region becomes demethylated during activation of naïve CD8+ T cells by anti-CD3/anti-CD28 antibodies and IL2. Finally, we conducted a genome-wide DNA methylation analysis comparing CD8+ T cells from CLL patients against healthy donors and identified additional differentially methylated genes with known immune regulatory functions including CCR6 and KLRG1. Taken together, our findings reveal the occurrence of epigenetic reprogramming taking place within CLL patient CD8+ T cells and highlight the potential mechanism of how immunosuppression is accomplished in CLL.
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影响因子：
20.3
作者：
McClanahan, Fabienne;Riches, John C.;Gribben, John G.
通讯作者：
Gribben, John G.
DOI：
10.1073/pnas.0901166106
发表时间：
2009-04-14
影响因子：
11.1
作者：
Gorgun, Gullu;Ramsay, Alan G.;Gribben, John G.
通讯作者：
Gribben, John G.
影响因子：
5.8
作者：
Goethert, Joachim Rudolf;Eisele, Lewin;Duerig, Jan
通讯作者：
Duerig, Jan
影响因子：
15.9
作者：
Ramsay, Alan G.;Johnson, Amy J.;Gribben, John G.
通讯作者：
Gribben, John G.
影响因子：
20.3
作者：
Mayr, C;Bund, D;Wendtner, CM
通讯作者：
Wendtner, CM