KSHV infection drives poorly cytotoxic CD56-negative natural killer cell differentiation in vivo upon KSHV/EBV dual infection

Nicole Caduff, Donal McHugh, Lisa Rieble, Catherine S. Forconi, John M. Ong'echa, Peter O. Oluoch, Ana Raykova, Anita Murer, Michelle Böni, Lara Zuppiger, Thomas F. Schulz, David J. Blackbourn, Obinna Chijioke, Ann M. Moormann, Christian Münz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Herpesvirus infections shape the human natural killer (NK) cell compartment. While Epstein-Barr virus (EBV) expands immature NKG2A+ NK cells, human cytomegalovirus (CMV) drives accumulation of adaptive NKG2C+ NK cells. Kaposi sarcoma-associated herpesvirus (KSHV) is a close relative of EBV, and both are associated with lymphomas, including primary effusion lymphoma (PEL), which nearly always harbors both viruses. In this study, KSHV dual infection of mice with reconstituted human immune system components leads to the accumulation of CD56CD16+CD38+CXCR6+ NK cells. CD56CD16+ NK cells were also more frequently found in KSHV-seropositive Kenyan children. This NK cell subset is poorly cytotoxic against otherwise-NK-cell-susceptible and antibody-opsonized targets. Accordingly, NK cell depletion does not significantly alter KSHV infection in humanized mice. These data suggest that KSHV might escape NK-cell-mediated immune control by driving CD56CD16+ NK cell differentiation.

Original languageEnglish
Article number109056
Number of pages20
JournalCell Reports
Issue number5
Publication statusPublished - 4 May 2021

Bibliographical note

Funding Information:
This research was supported in part by Cancer Research Switzerland , Switzerland ( KFS-4091-02-2017 ); KFSP-PrecisionMS and HMZ ImmunoTargET of the University of Zurich , Switzerland; the Cancer Research Center Zurich , Switzerland; the Vontobel Foundation , Switzerland; the Baugarten Foundation , Switzerland; the Sobek Foundation , Germany; the Swiss Vaccine Research Institute , Switzerland; Roche , Switzerland; Novartis , Switzerland; and the Swiss National Science Foundation , Switzerland ( 310030B_182827 and CRSII5_180323 ). A.M.M. was funded by a National Institutes of Health , United States, grant ( R01 CA189806 ). N.C. was supported by a career advancement grant from the University of Zurich , Switzerland ( FK-18-026 ). D.M. and M.B. were supported by MD-PhD fellowships from the Swiss National Science Foundation , Switzerland, and the Swiss Academy of Medical Sciences , Switzerland ( 323530_145247 and 323630_19938 ).


  • CD56-negative NK cells
  • EBV
  • Epstein-Barr virus
  • humanized mouse model
  • Kaposi sarcoma-associated herpesvirus
  • KSHV
  • natural killer cells


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