CD137 expression is induced by Epstein-Barr virus infection through LMP1 in T or NK cells and mediates survival promoting signals.
CD137 expression is induced by Epstein-Barr virus infection through LMP1 in T or NK cells and mediates survival promoting signals.
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DOI：
10.1371/journal.pone.0112564
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Arai A
中科院分区：
文献类型：
--
作者：
Yoshimori M;Imadome K;Komatsu H;Wang L;Saitoh Y;Yamaoka S;Fukuda T;Kurata M;Koyama T;Shimizu N;Fujiwara S;Miura O;Arai A
为了阐明EB病毒(EBV)阳性T细胞或NK细胞肿瘤的发生机制，我们重点研究了共刺激受体CD137。我们检测到CD137基因及其蛋白在EBV阳性的T或NK细胞系中的高表达，与EBV阴性的细胞系相比。EBV阳性T细胞或NK细胞增生性疾病(EBV-T/NK-LPDs)患者的EBV阳性细胞的CD137基因表达也显著高于健康献血者的对照细胞。在IL-2的存在下，EBV-T/NK-LPDs患者血清中CD137蛋白表达上调，而正常人对照细胞中CD137蛋白表达不上调。在体外，EBV感染MOLT4细胞可诱导内源性CD137表达。IL-2在EBV-T/NK-LPDs细胞中瞬时表达LMP1可诱导T细胞和NK细胞内源性CD137基因表达。为了检测CD137在体内的表达，我们使用了静脉注射患者细胞产生的EBV-T/NK-LPDs异种移植模型。我们在它们的组织病变中发现了EBV阳性和CD8阳性的T细胞，以及CD137配体阳性的细胞。此外，我们还用免疫荧光染色检测了模型皮损中EBV感染细胞上CD137的表达。最后，CD137刺激抑制了依托泊苷诱导的细胞死亡，不仅在EBV阳性T或NK细胞系中，而且在患者的细胞中也是如此。这些结果表明，EBV通过LMP1上调CD137的表达，促进T或NK细胞的存活，从而导致EBV阳性T/NK细胞肿瘤的发生。
To clarify the mechanism for development of Epstein-Barr virus (EBV)-positive T- or NK-cell neoplasms, we focused on the costimulatory receptor CD137. We detected high expression of CD137 gene and its protein on EBV-positive T- or NK-cell lines as compared with EBV-negative cell lines. EBV-positive cells from EBV-positive T- or NK-cell lymphoproliferative disorders (EBV-T/NK-LPDs) patients also had significantly higher CD137 gene expression than control cells from healthy donors. In the presence of IL-2, whose concentration in the serum of EBV-T/NK-LPDs was higher than that of healthy donors, CD137 protein expression was upregulated in the patients' cells whereas not in control cells from healthy donors. In vitro EBV infection of MOLT4 cells resulted in induction of endogenous CD137 expression. Transient expression of LMP1, which was enhanced by IL-2 in EBV-T/NK-LPDs cells, induced endogenous CD137 gene expression in T and NK-cell lines. In order to examine in vivo CD137 expression, we used EBV-T/NK-LPDs xenograft models generated by intravenous injection of patients' cells. We identified EBV-positive and CD8-positive T cells, as well as CD137 ligand-positive cells, in their tissue lesions. In addition, we detected CD137 expression on the EBV infected cells from the lesions of the models by immune-fluorescent staining. Finally, CD137 stimulation suppressed etoposide-induced cell death not only in the EBV-positive T- or NK-cell lines, but also in the patients' cells. These results indicate that upregulation of CD137 expression through LMP1 by EBV promotes cell survival in T or NK cells leading to development of EBV-positive T/NK-cell neoplasms.
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