PMC:7200337 / 26025-27804
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7200337","sourcedb":"PMC","sourceid":"7200337","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7200337","text":"The immune checkpoint NKG2A is increased on NK cells and CD8 T cells from COVID-19 patients (Zheng et al., 2020b). NKG2A inhibits cell cytotoxicity by binding the non-classical HLA-E molecule (Braud et al., 1998, Brooks et al., 1997), and this interaction is strongly correlated with poor control of HIV-1 infection (Ramsuran et al., 2018). Genes encoding the inhibitory receptors LAG3 and TIM3 are also upregulated in NK cells from COVID-19 patients (Wilk et al., 2020, Hadjadj et al., 2020). Thus, increased immune checkpoints on NK cells might contribute to viral escape. Additionally, COVID-19 patients have higher plasma concentrations of IL-6 (Huang et al., 2020b), which significantly correlate with lower NK cell numbers (Wang et al., 2020d, Wang et al., 2020f). In vitro stimulation by IL-6 and soluble IL-6 receptor has previously revealed impaired cytolytic functions (perforin and granzyme B production) by healthy donor NK cells, which can be restored following addition of tocilizumab (IL-6R blockade) (Cifaldi et al., 2015). TNF-α is also upregulated in the plasma of COVID-19 patients (Huang et al., 2020b), and ligand-receptor interaction analysis of peripheral blood scRNA-seq data suggests that monocyte-secreted TNF-α might bind to its receptors on NK cells (Guo et al., 2020). TNF-α is known to contribute to NK cell differentiation (Lee et al., 2009), which includes downregulation of NKp46 (Ivagnès et al., 2017), though no effect of TNF-α or IL-6 on NK cell-mediated ADCC has been reported so far. Collectively, these data suggest that crosstalk with monocytes might impair NK cell recognition and killing of SARS-CoV-2-infected cells, and antibodies targeting IL-6 and TNF-signaling may benefit enhanced NK cell functions in COVID-19 patients (Figure 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