title: Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1.
abstract: 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 EBV latent 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.
authors: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors: Jiun-Han
authors: JH
authors: Lin
authors: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors: Ju-Yin
authors: JY
authors: Lin
authors: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors: Ya-Ching
authors: YC
authors: Chou
authors: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors: Mei-Ru
authors: MR
authors: Chen
authors: Department of Otolaryngology, and.
authors: Te-Huei
authors: TH
authors: Yeh
authors: Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors: Chung-Wu
authors: CW
authors: Lin
authors: Research Center for Emerging Viral Infections, Graduate Institute of Medical Biotechnology, and Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors: Sue-Jane
authors: SJ
authors: Lin
authors: Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
authors: Ching-Hwa
authors: CH
authors: Tsai
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D015536:Down-Regulation; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006689:Hodgkin Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D058127:Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000949:Histocompatibility Antigens Class II; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D058127:Transcription Factor 3; D014763:Viral Matrix Proteins; D000099232:Proto-Oncogene Protein Spi-1; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C083728:MHC class II transactivator protein