Human cytomegalovirus activates natural killer cells


Human cytomegalovirus (HCMV) is a ubiquitous β-herpesvirus infecting most of the adult human population. Infection of healthy individuals is generally innocuous, but can result in mononucleosis-like or other organ-specific symptoms. Following resolution of primary infection HCMV persists in a mostly dormant state, but can be reactivated though the co-ordinated actions of multiple HCMV-encoded and host-derived gene products.  One of the major immune cell types responding to HCMV infection are Natural Killer (NK) cells. As reported in previous publications, redistribution of the NK cell repertoire occurs following HCMV infection. This results in more NK cells expressing the maturation marker CD57 and lectin-like NKG2C activating receptor. Levels of CD16 are elevated, while levels of NKG2A inhibitory receptors and natural cytotoxicity receptors (NCRs) NKp46 and NKp30 are reduced. These NK cells are apparently adapted towards more efficient antibody-dependent activation. Redistribution of cell surface receptors and emergence of NK cells with characteristics of adaptive immunity indicate formative interactions between HCMV and NK cells during acute and chronic infection.

Virokine CMV interleukin-10 (cmvIL-10), a homologue of human IL-10 (hIL-10), is encoded by the UL-111a HCMV gene and is expressed as multiple variants depending on the active or latent infection phase of the virus. The effect of cmvIL-10 has been well studied on human T-cells, macrophages, dendritic cells, B-cells and monocytes but its influence on NK cells was not explored prior to the study described below. A recent publication in the Journal of Leukocyte Biology discusses functional changes induced in NK cells by exposure to cmvIL-10. Canadian researchers at Memorial University of Newfoundland, PhD candidate Kayla Holder and Professor Michael Grant, investigated the effect of cmvIL-10 on functional and phenotypic alterations in NK cells. NK cells were exposed to cmvIL-10 for short periods to investigate immediate alterations in the cells.

The researchers utilized peripheral blood mononuclear cells (PBMC) as a source of NK cells for the study and noticed a significant enhancement of cytotoxicity in either PBMC or purified NK cells when exposed to full-length recombinant cmvIL-10 over the course of 5 h killing assays. The impact on NK cell cytotoxicity from exposure of cmvIL-10 was rapid and concentration dependent. They used polyclonal anti-cmvIL-10 or monoclonal anti-IL-10 receptor (IL-10R) antibodies to neutralize these changes and demonstrate specificity of the interaction. The effects observed on NK cell cytotoxicity were independent of increased perforin synthesis or activating receptor up-regulation. The percentage of NK cells actually expressing IL-10R was low and correlated directly with the extent of increase in CD16-induced degranulation of NK cells after exposure to cmvIL-10. However, there were no alterations in the phenotype of NK cells noticed during short term cmvIL-10 exposure comparable to those seen in NK cells following in vivo HCMV infection.

The study by Kayla Holder and Professor Michael Grant is particularly important as it is the first detailed examination of cmvIL-10 effects on NK cell function. “Viral production of a protein that selectively activates a subset of antiviral NK cells is a counterintuitive effect for a pathogen, illustrating the complex relationship established between HCMV and the human immune system over millennia of co-evolution”. This study will help advance our understanding and knowledge of the complex and unique relationship between HCMV and NK cell biology, but more importantly, it paves the way for development of more innovative strategies to effectively engage NK cells against viral infections and cancer.

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Holder, A K., Grant, M D. Human cytomegalovirus IL-10 augments NK cell cytotoxicity, Journal of Leukocyte Biology (2019) 106, 447–454. DOI: 10.1002/JLB.2AB0418-158RR

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