Spatiotemporally Skewed Activation of Programmed Cell Death Receptor 1–Positive T Cells after Epstein-Barr Virus Infection and Tumor Development in Long-Term Fully Humanized Mice

Abstract

The Jackson Laboratory, which commercially distributes the nonobese diabetic Rag1 null IL2rg null mice.

CAR-T Cells Targeting Epstein-Barr Virus gp350 Validated in a Humanized Mouse Model of EBV Infection and Lymphoproliferative Disease

“…We have shown previously that fully humanized NRG mice transplanted with human CB CD34 + hematopoietic stem cells and infected with the preferentially latent recombinant EBV/B95-8 strain recapitulated EBV + LPD, and approximately one-third of the animals progressed to a pathology recapitulating DLBCL. 32 EBV latency and lytic cycles have been associated with development of aggressive EBV + DLBCL. 33 Similar observations were obtained from studies of humanized mice infected with EBV recombinant strains, showing that EBV pathogenesis resembling EBV + LPD requires early lytic viral protein expression to accelerate development toward an EBV + DLBCL phenotype.…”

“…To test whether CD4 + CAR + T- cells were required, sorted CD8 + CAR + T cells were administered alone or in combination with CD4 + CAR + T cells 1 day prior to EBV infection, keeping in mind that EBV infection is associated with inflammatory expansion of CD8 + T cells, resulting in decreased levels of CD4 + T cells. 32 Further, to avoid xeno-GVHD with non-specific human T cells, as a control, only phosphate-buffered saline (PBS) was administered to mice a day prior to EBV challenge. Two of three infection controls showed high progressive EBV spread from the spleen to the rest of the body until 5 weeks post infection (wpi), whereas for one mouse, the infection was very low and mostly restricted to the spleen ( Figures 3 C and 3D).…”

“…We have shown that long-term humanized NRG mice infected with EBV or HCMV show inflammatory responses associated with T cell expansion, activation, and release of cytokines in the plasma. 32 , 37 Therefore, we investigated whether a response to CAR-T cell administrations could show lower virus-associated inflammation. We quantitatively integrated analyses of infiltrating B and T lymphocyte types with their cell proliferation status by multiplexed immunohistochemistry analyses of spleen tissues for quantification of CD20 + Ki67 + and CD3 + Ki67 + cells.…”

Redirecting T Cells against Epstein–Barr Virus Infection and Associated Oncogenesis

“…Moreover, antibody mediated blocking of the co-receptors 2B4 or PD-1 on T cells also compromises EBV specific immune control in HIS mice [40,41]. Depending on the viral dose of infection, an IM like expansion of CD8 + T cells can be induced upon EBV infection, accumulating PD-1 + CD8 + T cells, with a germinal center homing phenotype reminiscent of tonsillar EBV specific CD8 + T cells in humans [41][42][43]. In good agreement with findings in primary immunodeficiency patients type I interferon and its main producers, plasmacytoid dendritic cells had little effect on EBV infection in HIS mice [44].…”

Probing Reconstituted Human Immune Systems in Mice With Oncogenic γ-Herpesvirus Infections

“…This 2B4 requirement was mainly on CD8 + T cells because their antibody mediated depletion did not further increase viral titers and tumor formation. In addition, CD8 + T cells with the inhibitory co-receptor PD-1 expanded during IM and in EBV infected humanized mice (33,63). They included both latent (LMP2) and lytic (BMLF1) EBV antigen specific CD8 + T cells.…”