NK Cell Subpopulations and Receptor Expression in Recovering SARS-CoV-2 Infection

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic of coronavirus disease (COVID-19). Whereas in most cases COVID-19 is asymptomatic or pauci-symptomatic, extremely severe clinical forms are observed. In this case, complex immune dysregulations and an excessive inflammatory response are reported and are the main cause of morbidity and mortality. Natural killer cells are key players in the control of viral infection, and their activity is regulated by a tight balance between activating and inhibitory receptors; an alteration of NK activity was suggested to be associated with the development of severe forms of COVID-19. In this study, we analyzed peripheral NK cell subpopulations and the expression of activating and inhibitory receptors in 30 patients suffering from neurological conditions who recovered from mild, moderate, or severe SARS-CoV-2 infection, comparing the results to those of 10 SARS-CoV-2-uninfected patients. Results showed that an expansion of NK subset with lower cytolytic activity and an augmented expression of the 2DL1 inhibitory receptor, particularly when in association with the C2 ligand (KIR2DL1-C2), characterized the immunological scenario of severe COVID-19 infection. An increase of NK expressing the ILT2 inhibitory receptor was instead seen in patients recovering from mild or moderate infection compared to controls. Results herein suggest that the KIR2DL1-C2 NK inhibitory complex is a risk factor toward the development of severe form of COVID-19. Our results confirm that a complex alteration of NK activity is present in COVID-19 infection and offer a molecular explanation for this observation. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-021-02517-4.

Innate immune responses to three doses of the BNT162b2 mRNA SARS-CoV-2 vaccine

“…Notably, the effect of the BNT162b1 mRNA vaccine on NK cells activation was also seen when individuals who underwent vaccination after having recovered from COVID-19 were analysed. Thus, recent results ( 36 ) indicate that the population of NK cells expressing the IL-T2 inhibitory receptor is increased in these patients, data presented here show that the second vaccine booster reduces such population, likely increasing NK cells activity. The effect of this vaccine on cytokine production by monocytes in previously infected individuals was different from that seen in individuals that had never been infected, as neither IFN-γ nor TNF were increased by vaccination in COVID-19-recovered subjects.…”

“…Hence, NK cells expressing the activation 2DS2 receptor were increased, whereas those expressing the inhibitory ILT-2 receptor were decreased by the vaccine protocol, indicating that the BNT162b1 vaccine gears NK-mediated immune responses toward activation. It is noteworthy to point out that very recent results show a reduction of CD56 dim and CD56 dim CD16 bright and an increase of ILT-2- expressing NK cells in patients suffering from severe COVID-19 ( 36 ). With the exception of ADCC, thus, also in the case of NK cells, multiple vaccine doses seem to result in the optimal stimulation of innate immunity-mediated antiviral responses.…”

Organ-Dysfunction Markers in Mild-to-Moderate COVID-19 Convalescents

“…During infection, NK cells may change their phenotype from CD56bright to CD56dim, or even CD56neg. Such cells express a less cytotoxic phenotype, with decreased expression of perforins and granzymes [40,41]. The other mechanism which can lead to decreased CD56 expression is a depletion in the number of NK cells in the peripheral blood of patients suffering from COVID-19 [42].…”

Distribution of KIR Genes and Their HLA Ligands in Different Viral Infectious Diseases: Frequency Study in Sicilian Population

“…Among the COVID-19 group, those with the severe type of disease showed a statistically significant increase in the frequency of haplotype A/A as well as a significant reduction in KIR2DS2 frequency compared to asymptomatic/paucisymptomatic patients [ 32 ]. Moreover, analysis of KIR expression showed a significant increase in 2DL1+ NK cells in severe compared to mild or moderate COVID-19 patients and SARS-CoV-2-uninfected controls [ 33 ].…”