Abnormality in the NK-cell population is prolonged in severe COVID-19 patients

Abstract

Background Our understanding of adaptive immune responses in COVID-19 patients is rapidly evolving, but information on the innate immune responses by natural killer (NK) cells is still insufficient. Objective We aimed to examine the phenotypic and functional status of NK cells and their changes during the course of mild and severe COVID-19. Methods We performed RNA sequencing (RNA-seq) and flow cytometric analysis of NK cells from patients with mild and severe COVID-19 at multiple time points in the course of the disease using cryopreserved peripheral blood mononuclear cells (PBMCs). Results In RNA-seq analysis, the NK cells exhibited distinctive features compared to healthy donors, with significant enrichment of pro-inflammatory cytokine-mediated signaling pathways. Intriguingly, we found that the unconventional CD56 dim CD16 neg (uCD56 dim ) NK cell population expanded in cryopreserved PBMCs from COVID-19 patients regardless of disease severity, accompanied by decreased NK cell cytotoxicity. The NK cell population was rapidly normalized alongside the disappearance of uCD56 dim NK cells and the recovery of NK cell cytotoxicity in mild COVID-19 patients, but this occurred slowly in severe COVID-19 patients. Conclusion The current longitudinal study provides a deep understanding of the NK cell biology in COVID-19.

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients

“…In the present study, we aimed to characterize the phenotypic and KIR expression changes in NK cells during COVID-19. Our results showed an overall reduction in total NK cells and an expansion of the CD56 dim CD16 neg NK cell subset in parallel with the depletion of the CD56 dim CD16 dim/bright NK cell subsets, in line with other reports [20][21][22][23]. Interestingly, the expansion of the CD56 dim CD16 neg NK cell subset was concomitant with the expansion of this subset positive for inhibitory KIR receptors 2DL1 and 2DL1/S1 in hospitalized COVID-19 patients.…”

“…On the other hand, the CD56 neg CD16 bright NK cell subset was found to be depleted in COVID-19 patients in our study; this subset is reported to be an unconventional cytotoxic mediator for chronic diseases [15]. NK cells participate in a complex network, interacting with dendritic cells as well as T and B cells through chemokines and a variety of cytokines involved in the differentiation and function of NK cells [23,30,31,38,39].…”

Prolonged enhancement of cytotoxic T lymphocytes in the post-recovery state of severe COVID-19

“…Our results suggest that long-term recovery of B lymphocytes might be related to the severity of illness and the current stage of recovery. The NK cell population is reported to be greatly altered in patients with acute COVID-19, with an expansion of the cytokine-producing NK cells and a decrease in the cytolytic NK cells responsible for innate immunity [ 3 ]. Although cytolytic NK cells recovered with improvement of the disease, the frequency of cytokine-producing NK cells remained elevated in severe COVID-19.…”

The effects of SARS-CoV-2 infection on modulating innate immunity and strategies of combating inflammatory response for COVID-19 therapy

“…In mild patients, the conventional CD65 dim CD16 pos NK cells appeared, and the cytotoxicity recovered in a short time. However, the process took longer in severe infected patients [ 134 ]. Patients with severe respiratory failure (SRF) may also show macrophage activation syndrome (MAS) with a prominent reduction in natural killer cells, CD19 lymphocytes, and CD4 lymphocytes [ 135 ].…”