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Danisch, S.* ; Slabik, C.* ; Cornelius, A.* ; Albanese, M. ; Tagawa, T. ; Chen, Y.-F. A. ; Krönke, N.* ; Eiz-Vesper, B.* ; Lienenklaus, S.* ; Bleich, A.* ; Theobald, S.J.* ; Schneider, A.* ; Ganser, A.* ; von Kaisenberg, C.* ; Zeidler, R. ; Hammerschmidt, W. ; Feuerhake, F.* ; Stripecke, R.*

Spatiotemporally skewed activation of PD-1 T cells after epstein barr virus infection and tumor development in long-term fully humanized mice.

Am. J. Pathol. 189, 521-539 (2019)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Immune-responses; Ebv; Reconstitution; Expression; Model; System; Chain; Stem

ISSN (print) / ISBN 0002-9440

e-ISSN 1525-2191

Journal American Journal of Pathology, The

Quellenangaben Volume: 189, Issue: 3, Pages: 521-539

Publisher Elsevier

Publishing Place Ste 800, 230 Park Ave, New York, Ny 10169 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Gene Vector (AGV)