Adoptive Transfer of EBV Specific CD8+ T Cell Clones Can Transiently Control EBV Infection in Humanized Mice

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.

A Hitchhiker's guide to humanized mice: new pathways to studying viral infections

“…most commonly derived from cord blood, fetal livers or granulocyte–macrophage colony‐stimulating factor (GM‐CSF) ‐mobilized peripheral blood (Fig. ) . Engraftment depends heavily on stem cell origin, injection route, HSC donor, background murine strain, irradiation status and engraftment age.…”

“…1). 6 Engraftment depends heavily on stem cell origin, injection route, HSC donor, background murine strain, irradiation status and engraftment age. Most haematopoietic lineages are engrafted, including several myeloid subsets.…”

Infection and immune control of human oncogenic γ-herpesviruses in humanized mice

“…R. Soc. B 374: 20180296 transactivation, it was shown that lytic EBV replication only transiently contributes to viral loads in immunocompetent humanized mice [40] (figure 1). However, lytic EBV replication can be increased by using viruses with similarities to those found in nasopharyngeal carcinoma [45,46].…”

“…B 374: 20180296 enables us to investigate the requirements for their development and immune control. High-dose EBV infection (10 5 infectious virus particles) leads to lymphoproliferative lesions in 20 -30% of the infected animals [8,40,41]. These tumours are B-cell lymphomas with latency III EBV gene expression which disseminate from the spleen to liver, kidney, lymph nodes and pancreas [8,39].…”

Immune control of oncogenic γ-herpesviruses

“…In these cell lines EBV antigen specificities that mediate protection are mostly ill-defined and it is assumed that T cells against transforming latent EBV antigens primarily mediate anti-tumor effects after adoptive transfer. Interestingly, recent studies have suggested that some EBV associated malignancies might benefit from lytic EBV infection [28,29] and that lytic EBV antigen specific CD4 + and CD8 + T cells might be able to contribute to EBV associated lymphoma suppression [29,30]. In good agreement, plasma EBV viral loads, which might in part result from virus shedding, correlate with the occurrence and progression of some EBV associated malignancies, including PTLD, Hodgkin’s lymphoma and nasopharyngeal carcinoma [31–33].…”