Abstract
Epstein Barr virus (EBV) infection expands CD8+ T cells specific for lytic antigens to high frequencies during symptomatic primary infection, and maintains these at significant numbers during persistence. Despite this, the protective function of these lytic EBV antigen-specific cytotoxic CD8+ T cells remains unclear. Here we demonstrate that lytic EBV replication does not significantly contribute to virus-induced B cell proliferation in vitro and in vivo in a mouse model with reconstituted human immune system components (huNSG mice). However, we report a trend to reduction of EBV-induced lymphoproliferation outside of lymphoid organs upon diminished lytic replication. Moreover, we could demonstrate that CD8+ T cells against the lytic EBV antigen BMLF1 can eliminate lytically replicating EBV-transformed B cells from lymphoblastoid cell lines (LCLs) and in vivo, thereby transiently controlling high viremia after adoptive transfer into EBV infected huNSG mice. These findings suggest a protective function for lytic EBV antigen-specific CD8+ T cells against EBV infection and against virus-associated tumors in extra-lymphoid organs. These specificities should be explored for EBV-specific vaccine development.
Highlights
IntroductionEpstein Barr virus (EBV) is a ubiquitous human c-herpesvirus that establishes persistent infection in more than 90% of the human adult population [1]
Symptomatic primary Epstein Barr virus (EBV) infection, called infectious mononucleosis, predisposes for some of these malignancies and is characterized by massive expansions of cytotoxic T cells, which are mostly directed against lytic EBV antigens that are expressed during virus particle production
We investigated the protective role of lytic EBV antigen specific T cells during EBV infection and the contribution of lytic EBV infection to virusassociated tumor formation
Summary
Epstein Barr virus (EBV) is a ubiquitous human c-herpesvirus that establishes persistent infection in more than 90% of the human adult population [1]. Latent infection leads to the expression of eight viral proteins and more than forty nontranslated RNAs. Latent infection leads to the expression of eight viral proteins and more than forty nontranslated RNAs This program is able to immortalize human B cells and is found in EBV associated tumors [2]. Human T cells recognize both latent and lytic EBV antigens with distinct hierarchies [4]. CD4+ T cells often recognize late lytic EBV antigens [7], while CD8+ T cells arise in response to early lytic antigens, including BMLF1 [8]. The expansion of these lytic EBV antigen-specific CD8+ T cells seems to follow viral load during symptomatic primary infection, called infectious mononucleosis, while latent EBV antigen-specific T cells peak during convalescence consistent with their involvement in viral immune control [4]. We aimed to evaluate the protective role of lytic EBV antigen specific CD8+ T cells in vitro and in vivo
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