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

• Published in: The American journal of pathology Vol. 189; no. 3; pp. 521 - 539
• Main Authors: 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, von Kaisenberg, Constantin, Zeidler, Reinhard, Hammerschmidt, Wolfgang, Feuerhake, Friedrich, Stripecke, Renata
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019; American Society for Investigative Pathology
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Epstein-Barr Virus Infections - immunology; Epstein-Barr Virus Infections - pathology; Herpesvirus 4, Human - immunology; Humans; Lymphocyte Activation; Mice; Mice, Mutant Strains; Neoplasm Proteins - immunology; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - virology; Programmed Cell Death 1 Receptor - immunology
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2018.11.014

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.