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Am J Pathol. 2019 Mar;189(3):521-539. doi: 10.1016/j.ajpath.2018.11.014. Epub 2018 Dec 26.

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.

Author information

1
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; Laboratory of Regenerative Immune Therapies Applied, Excellence Cluster REBIRTH and German Centre for Infection Research, Partner Site Hannover, Hannover, Germany.
2
Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health and German Centre for Infection Research, Partner Site Munich, Munich, Germany.
3
Institute of Pathology, Hannover Medical School, Hannover, Germany.
4
Institutes for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
5
Laboratory Animal Science, Hannover Medical School, Hannover, Germany.
6
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
7
Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, Hannover, Germany.
8
Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health and German Centre for Infection Research, Partner Site Munich, Munich, Germany; Department of Otorhinolaryngology, Klinikum der Universität and German Centre for Infection Research, Partner Site Munich, Munich, Germany.
9
Institute of Pathology, Hannover Medical School, Hannover, Germany; Institute for Neuropathology, University Clinic Freiburg, Freiburg, Germany.
10
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; Laboratory of Regenerative Immune Therapies Applied, Excellence Cluster REBIRTH and German Centre for Infection Research, Partner Site Hannover, Hannover, Germany. Electronic address: renata@mh-hannover.de.

Abstract

Humanized mice developing functional human T cells endogenously and capable of recognizing cognate human leukocyte antigen-matched tumors are emerging as relevant models for studying human immuno-oncology in vivo. Herein, mice transplanted with human CD34+ stem cells and bearing endogenously developed human T cells for >15 weeks were infected with an oncogenic recombinant Epstein-Barr virus (EBV), encoding enhanced firefly luciferase and green fluorescent protein. EBV-firefly luciferase was detectable 1 week after infection by noninvasive optical imaging in the spleen, from where it spread rapidly and systemically. EBV infection resulted into a pronounced immunologic skewing regarding the expansion of CD8+ T cells in the blood outnumbering the CD4+ T and CD19+ B cells. Furthermore, within 10 weeks of infections, mice developing EBV-induced tumors had significantly higher absolute numbers of CD8+ T cells in lymphatic tissues than mice controlling tumor development. Tumor outgrowth was paralleled by an up-regulation of the programmed cell death receptor 1 on CD8+ and CD4+ T cells, indicative for T-cell dysfunction. Histopathological examinations and in situ hybridizations for EBV in tumors, spleen, liver, and kidney revealed foci of EBV-infected cells in perivascular regions in close association with programmed cell death receptor 1-positive infiltrating lymphocytes. The strong spatiotemporal correlation between tumor development and the T-cell dysfunctional status seen in this viral oncogenesis humanized model replicates observations obtained in the clinical setting.

PMID:
30593822
DOI:
10.1016/j.ajpath.2018.11.014
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