NK Cells: A Powerful Squad Versus SARS-CoV-2

Abstract

The function of NK cells in cancer and viral infections is well documented and understood. NK cell activity, including cytokine secretion, cytotoxic activity, and the coordination of inhibitory and activating receptors, linking innate and adaptive immunity, among others, has been examined for numerous pathogens, including parasites, bacteria, and viruses. The emergence of the SARS-CoV-2 health crisis has exposed a deficiency in understanding the previously elucidated mechanisms; the rationale for the reported variability in symptomatology among COVID-19 patients is extensive and intricate. It is evident that NK cells exert a significant influence on symptom severity, and their absence, with the presence or absence of their surface receptors, elicits a tailored response to the virus. This overview examines the impact of NK cells on the progression of several viral diseases, emphasizing their involvement in the pathogenesis of SARS-CoV-2 via the activation of surface receptors.

Keywords: KIR; NK cells; SARS-CoV-2; lectin-type; receptors.

Figure 1

The functional activity of natural killer (NK) cells is tightly regulated by a finely balanced integration of activating and inhibitory signals, mediated through interactions between NK cell surface receptors and class I human leukocyte antigen (HLA) molecules on potential target cells. The outcome of this interaction depends on the specific repertoire and relative expression levels of these receptors. Two principal scenarios can be distinguished: (A) When inhibitory receptors predominate and effectively engage with their cognate HLA ligands on the target cell, a negative signal is transduced, leading to the suppression of NK cell cytotoxic activity and the preservation of the target cell, typically indicative of a healthy, non-infected state. (B) Conversely, if activating receptors prevail in the interaction with their respective HLA ligands, the balance shifts toward the activation of the NK cell, culminating in the targeted elimination of the infected or transformed cell through the release of cytolytic effector molecules. Created in BioRender. Alvarado Hernández, D. (2022) BioRender.com/f09s127.

Figure 2

The expression of surface receptors on NK cells is a crucial aspect of their development in the bone marrow. The process could be broadly summarized into three stages of maturation, the third being the one that commits the immature NK cell to turn into a cytotoxic lytic effector lymphocyte with the appearance of CD16+ and CD56+ surface markers. These receptors can be classified as either activating or inhibitory, depending on the signals triggered by their interaction with ligands (primarily HLA-I molecules). The left side of the image shows the main inhibitory receptors, while the right side highlights some of the most relevant activating receptors. Created in BioRender. Alvarado Hernández, D. (2022) BioRender.com/c06i351.

Figure 3

The killer cell immunoglobulin-like receptors (KIRs), members of the immunoglobulin superfamily, constitute a diverse and highly polymorphic group of surface receptors. They are classified based on the number of extracellular immunoglobulin-like domains (either two or three), the length of their cytoplasmic tail—long (L) or short (S)—and sequence homology. Structurally, KIRs with long cytoplasmic tails typically mediate inhibitory signals via immunoreceptor tyrosine-based inhibitory motifs (ITIMs), whereas those with short tails generally serve activating roles through association with adaptor molecules bearing immunoreceptor tyrosine-based activating motifs (ITAMs). These receptors are predominantly expressed on the CD56^dim/CD16⁺ subset of NK cells, which are principally responsible for executing cytotoxic functions. Created in BioRender. Alvarado Hernández, D. (2022) BioRender.com/f00c581.