IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter

Abstract

Epstein-Barr virus (EBV) is associated with a variety of human tumors. Although the EBV-infected normal B cells in vitro and the EBV-carrying B cell lymphomas in immunodeficient patients express the full set of latent proteins (type III latency), the majority of EBVassociated malignancies express the restricted type I (EBNA-1 only) or type II (EBNA-1 and LMPs) viral program. The mechanisms responsible for these different latent viral gene expression patterns are only partially known. IL-21 is a potent B cell activator and plasma cell differentiation-inducer cytokine produced by CD4 + T cells. We studied its effect on EBV-carrying B cells. In type I Burkitt lymphoma (BL) cell lines and in the conditional lymphoblastoid cell line (LCL) ER/ EB2-5, IL-21 potently activated STAT3 and induced the expression of LMP-1, but not EBNA-2. The IL-21-treated type I Jijoye M13 BL line ceased to proliferate, and this was paralleled by the induction of IRF4 and the down-regulation of BCL6 expression. In the type III LCLs and BL lines, IL-21 repressed the C-promoter-derived and LMP-2A mRNAs, whereas it up-regulated the expression of LMP-1 mRNAs. The IL-21-treated type III cells underwent plasma cell differentiation with the induction of Blimp-1, and high levels of Ig and Oct-2. IL-21 might be involved in the EBNA-2-independent expression of LMP-1 in EBV-carrying type II cells. In light of the fact that IL-21 is already in clinical trials for the treatment of multiple malignancies, the in vivo modulation of EBV gene expression by IL-21 might have therapeutic benefits for the EBV-carrying malignancies.Epstein-Barr virus | IL-21 | lymphoma | STAT3

T Cells Modulate Epstein-Barr Virus Latency Phenotypes during Infection of Humanized Mice

“…LMP1 is induced by CD4 ϩ T cell-derived cytokines like IL-4, IL-10, IL-13, and IL-21 (18)(19)(20), which is probably the mechanism through which the T cells provide help for the in vitro growth of the infected B cells. IL-6 is another cytokine known to be a growth factor for EBV-infected B cells (43).…”

“…For survival and proliferation of the EBV-carrying type IIa cells, inter-actions with the microenvironment are required (17). Results from our laboratory have shown that a number of cytokines (interleukin-4 [IL-4], IL-13, and IL-21) contribute to the induction of expression of LMP1 (18)(19)(20) and probably help the survival and proliferation of latency IIa cells in vivo.…”

Latency Type-Dependent Modulation of Epstein-Barr Virus-Encoded Latent Membrane Protein 1 Expression by Type I Interferons in B Cells

“…LMP-1 plays a central role in EBV biology, since it acts in part as a constitutively active CD40 receptor analog and is essential for B cell proliferation and transformation by EBV (24). In type III latency, EBNA-2 is the major transactivator of the LMP promoters, while in type II latency, depending on the cellular context, different cytokines , are responsible for the activation of LMP-1 transcription (20,26,27,28).Type I interferons (IFNs) are produced in relatively large amounts in response to pathogen sensing by the innate immune system (46). In addition to their direct antiviral activities, these proteins also have antiproliferative and immunomodulatory properties.…”

“…mal amounts of LMPs [1,4,22,23]), the type I BL lines Akata (45), Rael (32), and Jijoye-M13 (27), the type III BL line Raji (28), and the cord blood-derived LCL CBM1-Ral-STO, transformed with the Rael EBV strain (7). IFN-␣ treatment for 24 h led to the upregulation of LMP-1 protein expression in Jijoye-M13 cells and in all the BL lines carrying EBNA-2-deleted virus, while LMP-1 mRNA and protein levels did not increase in the other cell lines ( To analyze the kinetics and specificity of LMP-1 upregulation, LMP-1 mRNA and protein levels were measured together with LMP-2A and ISG56 mRNA expression in Daudi cells treated with IFN-␣ for 1, 3, 6, and 24 h (Fig.…”

New developments in the pathology of malignant lymphoma: a review of the literature published from October 2009 to January 2010

“…In EBV-associated lymphomas, latencies type I or II, both with a limited expression of EBV proteins, predominate. Kis et al [7] demonstrate that in type I latency, IL21 activates STAT 3, with expression of LMP1 but not EBNA2 and downregulation of proliferation. In type III latency, LMP-1 was upregulated as well, but LMP-2a was repressed.…”