3-4-1- NK cells
Multiple studies have reported reduced numbers of NK cells in the peripheral blood of COVID-19 patients, which is associated with the severity of the disease (Song, Xu, He, & Lu, 2020; Yu et al., 2020). Although lung NK cells are susceptible to infection with the influenza virus, they do not express angiotensin-converting enzyme 2 (ACE2) and are therefore unlikely to be directly infected by SARS-CoV-2 (Travaglini et al., 2020). However, frequencies of NK cells expressing CD16 and/or KIRs are decreased in the blood following SARS-CoV-2 and SARS-CoV infection, respectively (F. Wang et al., 2020). In vitro, CXCR3 ligands (CXCL9-11) are increased in SARS-CoV-2-infected human lung tissue (Hin Chu et al., 2020), and CXCR3-ligand-producing monocytes are expanded in the lungs of COVID-19 patients (Liao et al., 2020). This suggests that the CXCR3 pathway might facilitate NK cell recruitment from the peripheral blood to the lungs in the COVID-19 patients. Secretion of IgG during SARS-CoV-2 infection (Amanat et al., 2020) may induce CD56dim CD16+ NK cell activation through Fc receptor recognition of antibodies either bound to the surface antigens expressed on the infected cells or to the extracellular virions as immune complexes. Interaction with virus antigen causes both cytokine production by NK cells and lysis of infected cells through antibody-mediated cellular cytotoxicity (ADCC) (Von Holle & Moody, 2019). These findings suggest that triggering NK cell activation may not only contribute to the resolution of infection but also contribute to the cytokine storm in ARDS. Ex vivo NK cells from peripheral blood of COVID-19 patients have reduced intracellular expression of CD107a, granulysin, and granzyme B, suggesting impaired cytotoxicity, as well as an impaired production of cytokines (Wilk et al., 2020).
TNF-α is upregulated in the plasma of COVID-19 patients (Chaolin Huang et al., 2020), and it seems that the monocyte-secreted TNF-α might bind to its receptors on NK cells (Guo et al., 2020). It is also known to contribute to NK cell differentiation (Lee et al., 2009), and downregulation of NKp46. Evidence suggests that crosstalk with monocytes might impair NK cell recognition and killing of SARS-CoV-2-infected cells, and targeting IL-6 and TNF-signaling may improve NK cell functions in COVID-19 patients.