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.