The Evolutionary Arms Race between Virus and NK Cells: Diversity Enables Population-Level Virus Control

Savoy, Sarah K. A.; Boudreau, Jeanette E.

doi:10.3390/v11100959

Cited by 22 publications

(16 citation statements)

References 110 publications

(144 reference statements)

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“…Interestingly, KIR expression was absent on freshly isolated CD94 + ILCs, suggesting that killing is most likely regulated through CD94 itself. Since some viruses, (e.g., influenza, Epstein-Barr, and human Cytomegalovirus) have evolved specific NK cell evasion mechanisms by promoting engagement of inhibitory KIRs and thereby inactivating NK cells, the existence of these CD94 + ILCs could be an evolutionary adaptation [31]. Given that CD94 + ILCs do not express KIRs, and thus no inhibitory KIRs, they should be resistant to this type of viral immune mediated evasion and their cytotoxicity may be crucial in protection against such viruses.…”

Section: Discussionmentioning

confidence: 99%

Identification of human cytotoxic ILC3s

et al. 2021

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Human ILCs are classically categorized into five subsets; cytotoxic CD127−CD94+ NK cells and non‐cytotoxic CD127+CD94−, ILC1s, ILC2s, ILC3s, and LTi cells. Here, we identify a previously unrecognized subset within the CD127+ ILC population, characterized by the expression of the cytotoxic marker CD94. These CD94+ ILCs resemble conventional ILC3s in terms of phenotype, transcriptome, and cytokine production, but are highly cytotoxic. IL‐15 was unable to induce differentiation of CD94+ ILCs toward mature NK cells. Instead, CD94+ ILCs retained RORγt, CD127 and CD200R1 expression and produced IL‐22 in response to IL‐15. Culturing non‐cytotoxic ILC3s with IL‐12 induced upregulation of CD94 and cytotoxic activity, effects that were not observed with IL‐15 stimulation. Thus, human helper ILCs can acquire a cytotoxic program without differentiating into NK cells.

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Section: Discussionmentioning

confidence: 99%

Identification of human cytotoxic ILC3s

et al. 2021

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“…They can gather in large quantities to attack virus-infected or malignant cells without prior stimulation. 14 Aside from the strong cytotoxic activity against tumour cells and viruses, NK cells secrete a variety of cytokines (IFN-γ, TNF-α, GM-CSF and chemokines), participate early in the innate immune response, modulate the acquired immune response and act as a bridge linking the two immune responses. 15 – 17 Here, we first performed longitudinal analysis of lymphocyte subsets in IHCs undergoing PEG-IFN treatment, focusing on NK cells.…”

Section: Discussionmentioning

confidence: 99%

Contribution of NK cells to HBsAg seroconversion in inactive HBsAg carriers following pegylated IFN therapy

et al. 2020

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Our recent study showed a high rate of HBsAg seroconversion in inactive HBsAg carriers (IHCs) treated with pegylated IFN (PEG-IFN). To understand the immune-mediated component of the HBsAg seroconversion better, this study investigated the role of NK cells. A total of 44 IHCs were given 48 wk of PEG-IFN. Fifteen cases achieved HBsAg seroconversion (R group), whereas 29 failed (NR group). The proportion and activity (CD107α and IFN-γ production) of NK cells were measured before and during treatment. We found that the proportion of NK cells in the R group was higher than in the NR group at baseline and during PEG-IFN treatment, even when patients were matched for age, sex and treatment period. IFN- γ secretion and CD107α expression from NK cells in cases who achieved HBsAg seroconversion were significantly higher than patients matched for age, sex, HBsAg and treatment period in the NR group at baseline and during PEG-IFN treatment. We also found that in HBsAg seroconversion cases, NK cells activity increased after PEG-IFN treatment, especially before HBsAg seroconversion. These effects were not found in non-responders. In conclusion, we demonstrated that the increase of NK cells accompanied by enhanced activity during PEG-IFN treatment favoured HBsAg seroconversion for IHC, and that NK cells may play a role in HBV seroconversion.

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“…More than half of the HCMV genome encodes proteins with immunomodulatory functions (24,65), a large array of which can inhibit NK cell functions (13,66). However, despite recent advances in the characterization of the HCMV genome, the functional relevance of HCMV genetic variability remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variability of Human Cytomegalovirus Clinical Isolates Correlates With Altered Expression of Natural Killer Cell-Activating Ligands and IFN-γ

et al. 2021

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Human cytomegalovirus (HCMV) infection often leads to systemic disease in immunodeficient patients and congenitally infected children. Despite its clinical significance, the exact mechanisms contributing to HCMV pathogenesis and clinical outcomes have yet to be determined. One of such mechanisms involves HCMV-mediated NK cell immune response, which favors viral immune evasion by hindering NK cell-mediated cytolysis. This process appears to be dependent on the extent of HCMV genetic variation as high levels of variability in viral genes involved in immune escape have an impact on viral pathogenesis. However, the link between viral genome variations and their functional effects has so far remained elusive. Thus, here we sought to determine whether inter-host genetic variability of HCMV influences its ability to modulate NK cell responses to infection. For this purpose, five HCMV clinical isolates from a previously characterized cohort of pediatric patients with confirmed HCMV congenital infection were evaluated by next-generation sequencing (NGS) for genetic polymorphisms, phylogenetic relationships, and multiple-strain infection. We report variable levels of genetic characteristics among the selected clinical strains, with moderate variations in genome regions associated with modulation of NK cell functions. Remarkably, we show that different HCMV clinical strains differentially modulate the expression of several ligands for the NK cell-activating receptors NKG2D, DNAM-1/CD226, and NKp30. Specifically, the DNAM-1/CD226 ligand PVR/CD155 appears to be predominantly upregulated by fast-replicating (“aggressive”) HCMV isolates. On the other hand, the NGK2D ligands ULBP2/5/6 are downregulated regardless of the strain used, while other NK cell ligands (i.e., MICA, MICB, ULBP3, Nectin-2/CD112, and B7-H6) are not significantly modulated. Furthermore, we show that IFN-γ; production by NK cells co-cultured with HCMV-infected fibroblasts is directly proportional to the aggressiveness of the HCMV clinical isolates employed. Interestingly, loss of NK cell-modulating genes directed against NK cell ligands appears to be a common feature among the “aggressive” HCMV strains, which also share several gene variants across their genomes. Overall, even though further studies based on a higher number of patients would offer a more definitive scenario, our findings provide novel mechanistic insights into the impact of HCMV genetic variability on NK cell-mediated immune responses.

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The Evolutionary Arms Race between Virus and NK Cells: Diversity Enables Population-Level Virus Control

Cited by 22 publications

References 110 publications

Identification of human cytotoxic ILC3s

Identification of human cytotoxic ILC3s

Contribution of NK cells to HBsAg seroconversion in inactive HBsAg carriers following pegylated IFN therapy

Genetic Variability of Human Cytomegalovirus Clinical Isolates Correlates With Altered Expression of Natural Killer Cell-Activating Ligands and IFN-γ

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