NK-cell receptor modulation in viral infections

Abstract

Natural killer (NK) cells play a crucial role in controlling viral infections. The ability to kill infected cells without prior immunization, yet being tolerant to self, healthy cells, depends on the balance of germ-line encoded surface receptors. NK-cell receptors are divided into either activating, leading to activation of NK cell and its cytotoxic and pro-inflammatory activity, or inhibitory, providing tolerance for a target cell. The signals from inhibitory receptors dominate and NK-cell activation requires stimulation of activating receptors. In viral infections, NK-cell interaction with infected cells can result in activation, memory-like NK-cell differentiation, or NK-cell exhaustion, which constitutes one of the viral immune evasion mechanisms. All of these states are associated with the modulation of NK-cell receptor expression. In this review, we summarize the current knowledge of NK-cell receptors and their role in viral infection control, as well as the alterations of their expression observed in acute or chronic infections. We present recently discovered SARS-CoV-2-mediated modulation of NK-cell receptor expression and compare them with other human viral infections. Finally, since modulation of NK-cell receptor activation gives a promising addition to currently used antiviral therapies, we briefly discuss the clinical significance and future perspective of the application of agonists or antagonists of activating and inhibitory receptors, respectively. In sum, our review shows that although much is known about NK-cell receptor biology, a deeper understanding of NK-cell receptors role in viral infections is still needed.

Keywords: NK cells; NK-cell receptors; activating receptors; inhibitory receptors; viral infections.

Graphical Abstract

Figure 1.

NK-cell interaction with virus infected cell can result in activation, exhaustion, or memory-like NK-cell differentiation, associated with the changes of NK-cell receptor expression. In physiological conditions, NK-cell activates after contact with an infected cell (A) Viral infection can result in the development of memory-like NK-cell phenotype (B). Viral infection might also mediate NK-cell exhaustion state (C). Created with BioRender.com

Figure 2.

NK-cell receptor-associated inhibition of NK-cell function mediated by aberrant expression of the receptors or ligands. Created with BioRender.com