title: Interleukin-21 regulates expression of key Epstein-Barr virus oncoproteins, EBNA2 and LMP1, in infected human B cells.
abstract: Epstein-Barr virus (EBV) persists for the life of the host by accessing the long-lived memory B cell pool. It has been proposed that EBV uses different combinations of viral proteins, known as latency types, to drive infected B cells to make the transition from resting B cells to memory cells. This process is normally antigen-driven. A major unresolved question is what factors coordinate expression of EBV latency proteins. We have recently described novel type III latency EBV+ B cell lines (OCI-BCLs) that were induced to differentiate into late plasmablasts/early plasma cells in culture with interleukin-21 (IL-21), mimicking normal B cell development. The objective of this study was to determine whether IL-21-mediated signals also regulate the expression of key EBV latent proteins during this window of development. Here we show that IL-21-reduced gene and protein expression of growth-transforming EBV nuclear antigen 2 (EBNA2) in OCI-BCLs. By contrast, the expression of CD40-like, latent membrane protein 1 (LMP1) strongly increased in these cells suggesting an EBNA2-independent mode of regulation. Same results were also observed in Burkitt's lymphoma line Jijoye and B95-8 transformed lymphoblastoid cell lines. The effect of IL-21 on EBNA2 and LMP1 expression was attenuated by a pharmacological JAK inhibitor indicating involvement of JAK/STAT signalling in this process. Our study also shows that IL-21 induced transcription of ebna1 from the viral Q promoter (Qp).
authors.affiliation: Division of Stem Cell and Developmental Biology, Princess Margaret Hospital, Ontario Cancer Institute, University Health Network, Toronto, Canada M5G 2M9. danijela.konforte@utoronto.ca
authors.forename: Danijela
authors.initials: D
authors.lastname: Konforte
authors.forename: Nathalie
authors.initials: N
authors.lastname: Simard
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Paige
mesh_terms: D001402:B-Lymphocytes / Q000821:virology*; D002460:Cell Line; D019309:Epstein-Barr Virus Nuclear Antigens / Q000096:biosynthesis*; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007378:Interleukins / Q000502:physiology*; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis*; D014763:Viral Matrix Proteins / Q000096:biosynthesis*; D014764:Viral Proteins / Q000096:biosynthesis*; D000098546:Interleukin-21
chemical_list: C402641:EBNA-2 protein, Human herpesvirus 4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D007378:Interleukins; D009856:Oncogene Proteins, Viral; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D000098546:Interleukin-21; C417029:EBV-encoded nuclear antigen 1