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: 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

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• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: The American journal of pathology. - 189, 3 (2019) , 521-539, ISSN: 1525-2191

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2019
• Creator: Danisch, Simon ; Slabik, Constanze ; Cornelius, Angela ; Albanese, Manuel ; Tagawa, Takanobu ; Chen, Yen-Fu A. ; Krönke, Nicole ; Eiz-Vesper, Britta ; Lienenklaus, Stefan ; Bleich, André ; Theobald, Sebastian ; Schneider, Andreas ; Ganser, Arnold ; Kaisenberg, Constantin von ; Zeidler, Reinhard ; Hammerschmidt, Wolfgang ; Feuerhake, Friedrich ; Stripecke, Renata

Further information

• DOI: 10.1016/j.ajpath.2018.11.014
• URN: urn:nbn:de:bsz:25-freidok-1503890
• Rights: Der Zugriff auf das Objekt ist unbeschränkt möglich.