Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1

Blood. 2015 Apr 2;125(14):2228-38. doi: 10.1182/blood-2014-08-594689. Epub 2015 Jan 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Blotting, Western
  • Cells, Cultured
  • Down-Regulation
  • Epstein-Barr Virus Infections / immunology
  • Epstein-Barr Virus Infections / metabolism
  • Epstein-Barr Virus Infections / virology
  • Gene Expression Regulation*
  • Herpesvirus 4, Human / physiology
  • Histocompatibility Antigens Class II / chemistry*
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / metabolism
  • Hodgkin Disease / immunology
  • Hodgkin Disease / metabolism
  • Hodgkin Disease / pathology
  • Humans
  • Immunoenzyme Techniques
  • Lymphoproliferative Disorders / immunology
  • Lymphoproliferative Disorders / metabolism
  • Lymphoproliferative Disorders / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism*
  • Transcription Factor 3 / genetics*
  • Transcription Factor 3 / metabolism
  • Transcriptional Activation
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism*

Substances

  • EBV-associated membrane antigen, Epstein-Barr virus
  • Histocompatibility Antigens Class II
  • MHC class II transactivator protein
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Trans-Activators
  • Transcription Factor 3
  • Viral Matrix Proteins
  • proto-oncogene protein Spi-1