Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin's lymphoma cells mediates up-regulation of CCL20 and the migration of regulatory T cells
Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin's lymphoma cells mediates up-regulation of CCL20 and the migration of regulatory T cells
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DOI：
10.2353/ajpath.2008.070845
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发表时间：
2008-07-01
影响因子：
6
通讯作者：
Murray, Paul G.
中科院分区：
文献类型：
--
作者：
Baumforth, Karl R. N.;Birgersdotter, Anna;Murray, Paul G.
与 50% 的霍奇金淋巴瘤 (HL) 患者类似，肿瘤细胞中存在 Epstein-Barr 病毒 (EBV)，一种致癌性疱疹病毒。对 HL 肿瘤和细胞系进行微阵列分析后，我们发现 EBV 感染增加了原代霍奇金和里德-斯滕伯格细胞以及霍奇金和里德-斯滕伯格细胞衍生的细胞系中趋化因子 CCL20 的表达。此外，这种上调可能是由 EBV 核抗原 1 蛋白介导的。 EBV感染的HL细胞系上清液中较高水平的CCL20增加了表达FOXP3的CD4（+）淋巴细胞的迁移，FOXP3是调节性T细胞（Treg）的标志物，Treg是抑制效应CD4（+）和CD8（+）T细胞的专门CD4（+）T细胞。在 HL 中，Treg 数量的增加与 EBV 特异性免疫力的丧失相关。我们的结果确定了一种机制，EBV 可以通过诱导 CCL20 的表达将 Tregs 招募到 HL 的微环境中，从而阻止针对病毒感染的肿瘤群体的免疫反应。进一步研究 EBV 如何招募和修饰 Treg 不仅有助于我们了解病毒相关肿瘤的发病机制，而且有助于开发旨在操纵 Treg 活性的治疗策略。
In similar to 50% of patients with Hodgkin's lymphoma (HL), the Epstein-Barr virus (EBV), an oncogenic herpesvirus, is present in tumor cells. After microarray profiling of both HL tumors and cell lines, we found that EBV infection increased the expression of the chemokine CCL20 in both primary Hodgkin and Reed-Sternberg cells and Hodgkin and Reed-Sternberg cell-derived cell lines. Additionally, this up-regulation could be mediated by the EBV nuclear antigen 1 protein. The higher levels of CCL20 in the supernatants of EBV-infected HL cell lines increased the migration of CD4(+) lymphocytes that expressed FOXP3, a marker of regulatory T cells (Tregs), which are specialized CD4(+) T cells that inhibit effector CD4(+) and CD8(+) T cells. In HL, an increased number of Tregs is associated with the loss of EBV-specific immunity. Our results identify a mechanism by which EBV can recruit Tregs to the microenvironment of HL by inducing the expression of CCL20 and, by doing so, prevent immune responses against the virus-infected tumor population. Further investigation of how EBV recruits and modifies Tregs will contribute not only to our understanding of the pathogenesis of virus-associated tumors but also to the development of therapeutic strategies designed to manipulate Treg activity.