LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis
LMP1-deficient Epstein-Barr virus mutant requires T cells for lymphomagenesis
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DOI：
10.1172/jci76357
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发表时间：
2015-01-01
影响因子：
15.9
通讯作者：
Kenney, Shannon C.
中科院分区：
文献类型：
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作者：
Ma, Shi-Dong;Xu, Xuequn;Kenney, Shannon C.
eb病毒（EBV）感染在体外转化B细胞并与人类B细胞淋巴瘤相关。主要的EBV癌蛋白，潜伏膜蛋白1 (LMP1)，模拟组成活性CD40，是EBV转化的B细胞体外生长所必需的；然而，ebv阳性的弥漫性大B细胞淋巴瘤和Burkitt淋巴瘤通常表达很少或不表达LMP1。因此，即使在缺乏LMP1的情况下，EBV也可能促进人类淋巴瘤的发展和维持。本研究发现，将感染lmp1缺陷EBV的人脐带血单个核细胞注射到免疫缺陷小鼠体内可诱导B细胞淋巴瘤。在该模型中，淋巴瘤的发展需要脐带血中CD4(+)T细胞的存在，并被cd40阻断抗体抑制。相反，lmp1缺陷型EBV直接注射到移植了人胎儿CD34（+）细胞和人胸腺的小鼠中，建立了持续的潜伏期，但没有诱发淋巴瘤。在两种小鼠模型中，WT EBV诱导的淋巴瘤不需要在脐带血模型中共注射T细胞。综上所述，这些结果表明LMP1在体内对ebv诱导的淋巴瘤并不是必需的，并且表明T细胞在ebv阳性B细胞淋巴瘤形成中提供替代LMP1的信号。
Epstein-Barr virus (EBV) infection transforms B cells in vitro and is associated with human B cell lymphomas. The major EBV oncoprotein, latent membrane protein 1 (LMP1), mimics constitutively active CD40 and is essential for outgrowth of EBV-transformed B cells in vitro; however, EBV-positive diffuse large B cell lymphomas and Burkitt lymphomas often express little or no LMP1. Thus, EBV may contribute to the development and maintenance of human lymphomas even in the absence of LMP1. Here, we found that i.p. injection of human cord blood mononuclear cells infected with a LMP1-deficient EBV into immunodeficient mice induces B cell lymphomas. In this model, lymphoma development required the presence of CD4(+)T cells in cord blood and was inhibited by CD40-blocking Abs. In contrast, LMP1-deficient EBV established persistent latency but did not induce lymphomas when directly injected into mice engrafted with human fetal CD34(+) cells and human thymus. WT EBV induced lymphomas in both Mouse models and did not require coinjected T cells in the cord blood model. Together, these results demonstrate that LMP1 is not essential for EBV-induced lymphomas in vivo and suggest that T cells supply signals that substitute for LMP1 in EBV-positive B cell lymphomagenesis.