Defining the role of natural killer cells in COVID-19

Abstract

Natural killer (NK) cells are critical effectors of antiviral immunity. Researchers have therefore sought to characterize the NK cell response to coronavirus disease 2019 (COVID-19) and the virus that causes it, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The NK cells of patients with severe COVID-19 undergo extensive phenotypic and functional changes. For example, the NK cells from critically ill patients with COVID-19 are highly activated and exhausted, with poor cytotoxic function and cytokine production upon stimulation. The NK cell response to SARS-CoV-2 is also modulated by changes induced in virally infected cells, including the ability of a viral peptide to bind HLA-E, preventing NK cells from receiving inhibitory signals, and the downregulation of major histocompatibility complex class I and ligands for the activating receptor NKG2D. These changes have important implications for the ability of infected cells to escape NK cell killing. The implications of these findings for antibody-dependent NK cell activity in COVID-19 are also reviewed. Despite these advances in the understanding of the NK cell response to SARS-CoV-2, there remain critical gaps in our current understanding and a wealth of avenues for future research on this topic.

Fig. 1 |. Changes in NK cell phenotype induced by severe COVID-19.

Schematic heat map showing the relative expression of proteins on the cell surface or intracellular proteins in NK cells from healthy donors and patients with COVID-19. ‘−’ indicates negligible expression; ‘+/−’ indicates low or variable expression; ‘+’ indicates moderate expression; ‘++’ indicates high expression

Fig. 2 |. Mechanisms underlying NK cell activation, exhaustion and dysfunction in severe COVID-19.

Cartoon illustrating four possible mechanisms underlying NK cell activation and dysfunction in severe COVID-19: inhibition by anti-inflammatory cytokines (for example, TGFβ); exhaustion due to chronic stimulation by pro-inflammatory cytokines (for example, IFNα) and/or activating ligands (for example, ULBPs and CD112); receptor-mediated inhibition (for example, increased expression of NKG2A); and loss of activating receptor expression (for example, loss of NKG2D and DNAM-1).

Fig. 3 |. Mechanisms of ligand modulation by SARS-CoV-2 in infected cells.

Schematic summarizing known mechanisms by which SARS-CoV-2 modulates expression of ligands for NK cell receptors in infected cells. Pathways on the left side of the dashed vertical line result in a net activating effect on NK cells Pathways on the right side of the dashed vertical line result in a net inhibitory effect on NK cells. Question marks indicate effects whose mechanisms are as yet unknown. KLRK1 encodes NKG2D. TFs, transcription factors.

Fig. 4 |. The two-pronged escape of NK cell killing by SARS-CoV-2.

Cartoon summarizing the escape of NK cell killing by SARS-CoV-2 through modulation of both target and effector cells. NK cells from healthy donors efficiently lyse tumor target cells. Killing is reduced when these target cells are infected, as SARS-CoV-2 downregulates the ligands for activating receptors on infected cells. NK cells from patients with severe COVID-19 are impaired in their ability to lyse uninfected target cells due to exhaustion and loss of key activating receptors. NK cells from patients with severe COVID-19 are severely impaired in their ability to respond to infected target cells because of both ligand expression modulation on target cells and effector cell dysfunction.