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

doi:10.1016/j.celrep.2021.109056

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

Cell Rep. 2021 May 4;35(5):109056. doi: 10.1016/j.celrep.2021.109056.

Authors

Affiliations

¹ Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
² Division of Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
³ Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.
⁴ Division of Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA; Center for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya.
⁵ Institute of Virology, Hannover Medical School, Hannover and German Centre of Infection Research (DZIF), Hannover-Braunschweig Site, Hannover, Germany.
⁶ School of Biosciences and Medicine, University of Surrey, Guildford, UK.
⁷ Cellular Immunotherapy, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
⁸ Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland. Electronic address: christian.muenz@uzh.ch.

Abstract

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 CD56^-CD16⁺CD38⁺CXCR6⁺ NK cells. CD56^-CD16⁺ 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 CD56^-CD16⁺ NK cell differentiation.

Keywords: CD56-negative NK cells; EBV; Epstein-Barr virus; KSHV; Kaposi sarcoma-associated herpesvirus; humanized mouse model; natural killer cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Epstein-Barr Virus Infections / immunology*
Herpesvirus 8, Human / pathogenicity*
Humans
Killer Cells, Natural / immunology*
Mice

Grants and funding

R01 CA189806/CA/NCI NIH HHS/United States