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

Danisch, Simon; Slabik, Constanze; Cornelius, Angela; Albanese, Manuel; Tagawa, Takanobu; Chen, Yen-Fu A.; Krönke, Nicole; Eiz-Vesper, Britta; Lienenklaus, Stefan; Bleich, Andre; Theobald, Sebastian J.; Schneider, Andreas; Ganser, Arnold; Kaisenberg, Constantin von; Zeidler, Reinhard; Hammerschmidt, Wolfgang; Feuerhake, Friedrich und Stripecke, Renata (2019): 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. In: American Journal of Pathology, Bd. 189, Nr. 3: S. 521-539

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0002-9440
• Sprache: Englisch