Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1
Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1
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DOI：
10.1182/blood-2014-08-594689
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发表时间：
2015-04-02
期刊：
影响因子：
20.3
通讯作者：
Tsai, Ching-Hwa
中科院分区：
文献类型：
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作者：
Lin, Jiun-Han;Lin, Ju-Yin;Tsai, Ching-Hwa
致瘤性EB病毒（EBV）使用各种方法逃避宿主免疫应答并在B细胞中持续存在。这种持续性感染可能为这种病毒引发肿瘤形成提供机会。以EB病毒永生化淋巴母细胞系（LCL）为模型，发现EBV感染后B细胞中主要组织相容性复合物（MHC）II类分子和CD 74的表达受到抑制。II类反式激活因子（CIITA）是MHC II类相关基因的主要调节因子。正如预期的那样，CIITA在LCL中下调。我们发现CIITA的下调是由EBV 1潜在膜蛋白2A（LMP 2A）引起的，并由CIITA-PIII启动子驱动。此外，我们证明了LMP 2A介导的E47和PU。1例减少导致CIITA抑制。从机制上讲，LMP 2A免疫受体酪氨酸激活基序对E47和PU的抑制至关重要。1启动子活性，通过Syk，Src和磷脂酰肌醇3-激酶/Akt途径。使用shLMP 2A方法消除LCL中的LMP 2A显示E47、PU. 1、CIITA、MHC II类和CD 74是逆转的。这些数据表明，LMP 2A可以通过干扰E47/PU来降低MHC II类表达。1-CIITA途径。最后，我们证明了MHC II类可以在扁桃体和EBV阴性的霍奇金病中检测到，但在EBV相关的移植后淋巴组织增生性疾病和霍奇金病中检测不到。
Oncogenic Epstein-Barr virus (EBV) uses various approaches to escape host immune responses and persist in B cells. Such persistent infections may provide the opportunity for this virus to initiate tumor formation. Using EBV-immortalized lymphoblastoid cell lines (LCLs) as a model, we found that the expression of major histocompatibility complex (MHC) class II and CD74 in B cells is repressed after EBV infection. Class II transactivator (CIITA) is the master regulator of MHC class II-related genes. As expected, CIITA was downregulated in LCLs. We showed that downregulation of CIITA is caused by EBVl atent membrane protein 2A (LMP2A) and driven by the CIITA-PIII promoter. Furthermore, we demonstrated that LMP2A-mediated E47 and PU. 1 reduction resulted in CIITA suppression. Mechanistically, the LMP2A immunoreceptor tyrosine-based activation motif was critical for the repression of E47 and PU. 1 promoter activity via Syk, Src, and the phosphatidylinositol 3-kinase/Akt pathway. Elimination of LMP2A in LCLs using a shLMP2A approach showed that the expression levels of E47, PU. 1, CIITA, MHC class II, and CD74 are reversed. These data indicated that the LMP2A may reduce MHC class II expression through interference with the E47/PU. 1-CIITA pathway. Finally, we demonstrated that MHC class II may be detected in tonsils and EBV-negative Hodgkin disease but not in EBV-associated posttransplant lymphoproliferative disease and Hodgkin disease.