Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of the coronavirus disease 2019 (COVID-19) pandemic, spread rapidly across the globe. As of July 20, 2022, more than 562 million confirmed COVID-19 cases have been reported worldwide, with approximately 6 million deaths. Most COVID-19 patients experience mild symptoms or even asymptomatic; however, some patients rapidly progress to critical illness, including acute respiratory distress syndrome, sepsis, or multiple organ failure. The resolution of the disease requires coordinated efforts of the innate and adaptive immunity. Natural killer (NK) cells, the essential part of the innate immunity, are the first line of defense against invading pathogens and regulate downstream adaptive immune responses of T and B cells.
In healthy controls, NK cells account for approximately 5% to 15% of peripheral blood mononuclear cells and are usually divided into CD56bright and CD56dim NK cells based on NK cell lineage markers expression, including CD56 and CD16. CD56bright NK cells can secrete abundant cytokines and chemokines. The CD56dim NK cells, abundant in the blood, mainly execute cytolytic functions through direct contact or through antibody-dependent cell-mediated cytotoxicity. Given the essentially acute and self-limiting disease course of COVID-19, the innate immune system, including NK cells, plays a critical role in limiting viral replication and determining the outcome of the disease. However, NK cell dysregulation has been reported during SARS-CoV-2 infection, which may impair the ability of NK cells to curtail disease progression. Hence, in this review, changes in the phenotypes and functions of NK cells in COVID-19 patients, the potential roles of NK cells in the immune pathogenesis of COVID-19, and the application of NK cell–based therapeutics for COVID-19 patient treatment was described.
The alteration of NK cells during SARS-CoV-2 infection
NK cells during SARS-CoV-2 infection exhibited altered activation, exhaustion, and functional profiles, which were closely related to disease severity [Figure 1]. The details are as follows.
NK cell lymphopenia
Numerous studies showed that reduced frequency or absolute counts of peripheral NK cells were in COVID-19 patients compared with healthy controls,[5–10] and the further reduction in NK cells was observed in severe cases. The lower NK cell counts, the worse survival rates of patients and the longer duration of viral shedding have been observed. Viral loads dropped rapidly in hospitalized COVID-19 patients with normal NK cell counts (>40 NK cells per microliter). The reduction in circulating NK cells may be due to the increased apoptosis of NK cells, altered turnover, and homing to inflamed/infected tissues. Increased expression of CD95 and caspase-3, which indicate of apoptosis in NK cells, was reported in COVID-19 patients. Gene ontology analysis also revealed that the levels of apoptosis of NK cells were upregulated in COVID-19 patients. Nevertheless, NK cell counts could restore to normal level at the convalescent stage of COVID-19. Chemokine-dominant hypercytokinemia was reported in bronchoalveolar lavage fluid (BALF) in COVID-19 patients; thus, the elevated levels of chemokines in the lungs may attract the peripheral NK cells to the site of infection. In addition, single-cell sequencing analysis revealed that COVID-19 patients exhibited an increased proportion of NK cells in the BALF.[17,18]
Alteration of NK cell subsets
CD56neg (CD56-CD16+) NK cell is an “exhausted” NK cell subset that expanded during chronic infections, including human immunodeficiency virus 1 and hepatitis C virus. In acute SARS-CoV-2 infection, Bozzano et al. reported an increased percentage of CD56neg NK cells and a decreased percentage of CD56bright NK cells. In addition, the expansion of unconventional CD56dim CD16neg (uCD56dim) NK cells in cryopreserved peripheral blood mononuclear cells was observed from patients with COVID-19 irrespective of disease severity. In addition, the uCD56dim NK cells last longer in severe COVID-19 patients and exhibited a higher proliferation capacity and lower cytotoxic capacity than conventional CD56dim NK cells. Accordingly, there was a negative association between NK cell cytotoxicity and the relative proportion of uCD56dim NK cells.
Advances in single-cell technologies were used to profile genes at the single-cell level and to identify new cell subsets. Krämer et al. identified 6 NK cell subsets by single-cell RNA sequencing (scRNA-seq), of which inflamed CD56dim NK cells (high interferon [IFN]-related genes) and proliferating CD56dim NK cells (MKI67) were strongly overrepresented in severe patients compared with moderate patients. Similarly, Witkowski et al. also identified “proliferating NK cells” with high MKI67 expression and genes that regulate the cell cycle, with these “proliferating NK cells” being increased in severe patients. In contrast, the frequency of “late effector NK cells” with reduced expression of effector genes was reduced in severe patients, indicating the impaired function of NK cells.
Impaired NK cell effector function
NK cell effector function relies on the signals transferred by activating and inhibitory receptors. During SARS-CoV-2 infection, NK cell receptors exhibited impaired effector functions, especially in severe cases. NKG2A transduces inhibitory signals via engagement with the ligand HLA-E to inhibit NK cell function. The expression of NKG2A on NK cells was upregulated and was correlated with disease severity in patients with COVID-19,[15,24] and NKG2A expression remained abnormal in severe COVID-19 patients after recovery. CD39, a key ectoenzyme that cleaves extracellular ATP and ADP, lead to the generation of adenosine, thereby potentially inhibiting the function of the NK cells. High expression levels of CD39 were also observed in COVID-19 patients. Other well-characterized immune checkpoint inhibitory receptors on T cells, such as TIGIT, LAG-3, PD-1, and TIM-3, were also increased in the peripheral NK cells of COVID-19 patients. Furthermore, Wilk and colleagues showed that the exhaustion score of NK cells, which is based on the transcriptional expression of LAG3, PDCD1, and HAVCR2, is remarkably increased in COVID-19 patients. NK cell exhaustion was also demonstrated by the reduced frequencies of DNAM-1–, NKG2D–, and Siglec-7–expressing NK cells. Moreover, NKG2D expression could not be fully restored at the convalescence in the asymptomatic and moderate patients. The main antiviral ability of NK cells depends on the binding of the target cells and the export of cytotoxic granules into target cells or through the secretion of antiviral cytokines, including IFN-γ and tumor necrosis factor α (TNF-α). During viral infections, NK cells undergo phenotypic changes to reflect their effector potentials. In consistent with the exhausted phenotype of NK cells during SARS-CoV-2 infection, studies have shown that the function of NK cells was impaired. Numerous studies have demonstrated that the degranulation marker, CD107a, was decreased in COVID-19 cases when they were cocultured with K562.[12,15,27] Data are not consistent with regard to the profiles of cytotoxic molecules expression in COVID-19 cases. Zheng et al. reported a decreased frequency of granzyme B+ NK cells in COVID-19 cases. In contrast, researches have demonstrated that the expression of granzyme B and perforin increased in patients with COVID-19, particularly in severe COVID-19.[6,12] Although increased cytotoxic granules were reported, NK cells in severe cases were unable to form cellular conjugations to release cytotoxic granules into Vero E6 cells and Calu-3 cells in coculture experiments in vitro. CD56bright NK cells have weak cytotoxic activity; however, they can release a large number of different cytokines. Meanwhile, compared with controls, CD56bright NK cells exhibited higher expressions of granzyme B and perforin in moderate and severe COVID-19 patients. The arming of CD56bright NK cells with cytotoxic molecules positively related to clinical indices associated with disease severity, including Pao2/Fio2 ratio and the Sequential Organ Failure Assessment score. Some studies demonstrated that there were a decrease of TNF-α, IFN-γ, and interleukin 2 (IL-2) expression on NK cells of COVID-19 cases upon stimulation with K562 or PMA and ionomycin, and the inhibitory effect of SARS-CoV-2 infection on the cytokine-secreting ability of total NK cells and NK cell subsets was consistent across different studies.[13,15,27–29]
NK cell activation
NK cell activation is beneficial for infection control at certain levels; however, excess or durable activation may promote immunopathogenesis. During SARS-CoV-2 infection, the expression levels of CD69, HLA-DR, and CD38 were increased,[6,13] whereas no changes were observed in the expression of CD16, NKG2C, TRAIL, NKp46, and NKp30. scRNA-seq analysis of NK cells in BALF from COVID-19 patients confirmed the activated status of NK cells, and bioinformatics analysis revealed that NK cells showed an activated and inflamed profile in severe patients. Furthermore, the amount of tissue trafficking of CD103+ NK cells increased in COVID-19 cases. Similarly, CD103+ NK cells displayed pronounced CD69 expression, a marker for tissue residency and activation. Homing is also likely to be mediated by CCR2, CCR5, CXCR3, and CXCR6. Brownlie et al. showed that NK cells that express lung-homing receptors displayed increased activation markers compared with those without expression of lung-homing receptors.
Adaptive NK cells
In addition to being in the first line against viral infections, NK cells also elicit remarkably stronger secondary responses that resemble the memory characteristics of adaptive lymphocytes. Maucourant et al. described an increase in the number of adaptive-like NK cells in COVID-19 cases. They reported a significant expansion of adaptivelike NK cells with NKG2C and CD57 coexpression in patients with severe/critical COVID19. Similar findings were reported in 2 other studies.[27,31] However, it is unclear whether the accumulation of adaptivelike NK cells was due to SARSCoV2 infection or a human cytomegalovirus (HCMV)–driven bystander phenomenon in severe patients. Individuals with HCMV infection seemed to be more common in severe disease, with some studies reporting that HCMV reactivation occurred in the lungs of ventilator-treated COVID19 patients.
NK cell roles in SARS-CoV-2 infection
NK cell roles in hyper-inflammation
In acute SARS-CoV-2 infection, lung damage can be directly mediated by virus-induced destruction of pneumocytes, by hyperactive immune responses, or both. Hypercytokinemia plays an essential part in the COVID-19 disease progression. Studies demonstrated that the levels of serum inflammatory markers, such as ferritin, C-reactive protein (CRP), d-dimer, and neutrophil-to-lymphocyte ratio were increased in patients with severe diseases.[35–38] A study also showed that high levels of IL-6, TNF-α, and IL-8 of patients’ serum at admission could predict the survival of COVID-19 patients. High-level inflammatory cytokines have been reported in the lungs, where intense viral replication occurs. RNA sequencing of BLAF from COVID-19 patients revealed that CCL2, CXCL10, CCL3, and CCL4 were highly upregulated. In addition, postmortem lung tissues from COVID-19 patients displayed increased levels of CCL2, CCL8, and CCL11 than those from healthy lung tissues.[16,41] Interestingly, NK cells also displayed an inflammatory phenotype under stimuli of inflammation. ScRNA-seq analysis uncovered an elevated proportion of inflamed CD56dim NK cells that expressed high levels of IFN-related genes. Increased frequency of “inflammatory” CD34+ DNAM-1briCXCR4+ NK cell precursors in the circulation of COVID-19 patients was observed, and severe disease progression was directly related to the fractions of CD34+ DNAM-1briCXCR4+ precursors. NK cell is main source of IFN-γ during early viral infection, and it has been reported that IFN-γ synergize with TNF-α to trigger tissue damage and cytokine shock syndrome during SARS-CoV-2 infection. In addition, the production of IFN-γ by NK cells has been reported to be responsible for the acute lung immune injury during respiratory syncytial virus infection. What is more, the depletion of NK cells during high dose of influenza virus infection reduced the lung damage. Thus, the production of IFN-γ by hyperactivated NK cells from severe COVID-19 patients might amplify inflammatory response by promoting the activation of macrophage and contribute to the occurrence of hypercytokinemia and lung damage thereafter. The inflammatory milieu can also impair the effector functions of NK cells. Previously, IL-6 and IL-8 were shown to impair the function of NK cells via a STAT-3 dependent pathway. In addition, the continuous exposure of NK cells to inflammatory molecules, such as IL-15, may result in hyporesponsiveness of NK cells to subsequent stimulation. In addition, serum from severe patients can inhibit NK cell function in a transforming growth factor beta (TGFβ)-dependent manner, and NK cell–mediated inhibition of SARS-CoV-2 viral replication in vitro was significantly abrogated by TGFβ. Furthermore, NK cells from severe cases showed strong and long-term TGFβ-controlled transcriptional reprogramming, especially the downregulation of genes involved in NK cell cytotoxicity. However, in moderate COVID-19 cases, a TNF-α–driven gene expression profiles was observed in NK cells [Figure 1]. The negative correlation between NK cell function and inflammation has also been observed in clinical samples. One study found that the total number of CD56dim NK cells was negatively associated with CRP levels. Negative correlations were also observed between NK cells expressing CD107a and IFN-γ and CRP. Furthermore, elevated levels of IL-6 were negatively related to the proportion of NK cells expressing granzyme A.
NK cell roles in viral clearance and convalescence
As mentioned previously, NK cell numbers are closely correlated with viral load decline[11,12]; however, the diversity of NK cell receptor repertoires has been demonstrated to be negatively correlated with the viral clearance rate. Furthermore, a study examining NK cell transcriptomic signatures showed an association between PRF1 and DDIT4 expression, which indicate NK cell cytotoxic and DNA repair marker, respectively, and patient improvement. Collectively, NK cells are closely related to viral clearance and COVID-19 recovery. Meanwhile, due to the inflammation caused by SARS-CoV-2 infection, the early upregulation of TGFβ in patients with severe COVID-19 and the NK cell–mediated repression of SARS-CoV-2 replication were compromised. Persistent viral replication in type II pneumocytes may also continuously promote the activation of macrophages and neutrophils, and the secretion of inflammatory cytokines and chemokines. Thus, more leukocytes may be recruited to further propagate the inflammatory response. The exacerbated inflammatory milieu may also further impair the antiviral effect of NK cells,[50,51] thus creating a vicious cycle. Collectively, dysregulated immune systems, including impaired NK cells, may lead to the development of hypercytokinemia and acute respiratory distress syndrome.
NK cell roles in lung fibrosis
SARS-CoV-2 can cause long-lasting or persistent pulmonary fibrosis. A study reported that patients receiving mechanical ventilation had more fibrotic changes than those who did not, 4 months after admission. Pulmonary fibrosis was observed in approximately half of the survivors infected with SARS-CoV-2, and a higher risk of developing pulmonary fibrosis occurred in severe patients. NK cells may control fibrotic reprogramming and elimination of prefibrotic cells. Krämer and colleagues reported that NK cells from severe COVID-19 cases displayed a reduced ability to inhibit the expression of the profibrotic genes, COL1A1 and ACTA-2, in fibroblasts. In addition, compared with moderate COVID-19 patients and controls, NK cells were unable to induce apoptosis in human lung fibroblasts in severe patients. In addition, TGFβ, known to promote fibrosis, is elevated in severe COVID-19 cases. Serum TGFβ from severe patients can also severely inhibit NK cell function. These data suggest that modulating NK cells might be a promising way to prevent lung fibrosis.
In summary, SARS-CoV-2 infection leads to impaired NK cell functions, including reduced antiviral and antifibrosis abilities, which may be closely linked to the development of severe COVID-19.
Adoptive NK cell therapy in COVID-19
Adoptive NK cell therapy has been proven to be safe and beneficial for cancer treatment.[55,56] Previous studies showed that there was a reduction of circulating NK cell numbers, and their ability to inhibit viral replication and lung fibrosis was impaired in COVID-19 cases. Thus, using NK cells to enhance antiviral immunity in the host is a viable therapy. To date, several registered clinical trials, Clinicaltrial.gov, applied adoptive NK cell therapy in patients infected with SARS-CoV-2 [Table 1],[57–59] including allogeneic NK cell infusion (NCT04344548), NK cells from placenta-derived cord blood (NCT04280224, NCT04365101), umbilical cord blood transfusion (NCT04324996), CD34+ hematopoietic stem cell–derived NK cell therapy (NCT04900454), and expanded ex vivo NK cell infusion (NCT04797975). These clinical trials focused primarily on the safety and preliminary efficacy of NK cell therapy in COVID-19 patients.
Table 1 -
Clinical trials of adoptive natural killer cell therapy
||Sources of NK cells
||CD34+ hematopoietic stem cells
||A single dose; IV
||The safety and tolerability
||Biological: placenta-derived cord blood NK Cells
||Placenta-derived cord blood
||Twice a week; IV
(0.1–2) ×10E7 cells/kg body weight
|The safety and efficacy
||Phase 1 Phase 2
||Common, severe, and critical
||Biological: NK cells, IL15-NK cells, NKG2D CAR-NK cells, ACE2 CAR-NK cells, NKG2D-ACE2 CAR-NK cells
||Umbilical cord blood
||Once a week; IV
1 × 10E8 cells/kg body weight
|The efficacy, the safety and tolerability
||Phase 1 Phase 2
||Biological: T memory cells and NK cells
||A single dose; IV
||The safety, tolerability, reactivity, and efficacy
||Active not recruiting
||Phase 1 Phase 2
||Placental CD34+ cells
||3 doses; IV
||The safety and efficacy
||Not yet recruiting
||Biological: NK cell infusion
||One dose; IV
1 × 10E6 cells/kg body weight
5 × 10E6 cells/kg body weight
1 × 10E7 cells/kg body weight
|The safety and efficacy
||Phase 1 Phase 2
||Biological: allogeneic NK transfer
||3 doses; IV
||The safety and immunogenicity
||Phase 1 Phase 2
||Mild to moderate
||Expanded ex vivo NK cells (KDS-1000)
||Low Dose, 2 × 10E8 cells/dose
High Dose, 1 × 10E9 cells/dose
COVID-19: coronavirus disease 2019; NK: natural killer; NKG2D: natural killer cell group 2D; CAR: chimeric antigen receptor; ACE2: angiotensin converting enzyme 2; CD34: cluster differentiation 34; IV: intravenous; “-”: not available.
Previous studies demonstrated that the timing of adoptive transfer of NK cells may be critical. Mostafa et al. reported that the early infusion of NK cells in mice is critical, and delayed transfer of NK cells resulted in increased lung infection and morbidity. In the COVID-19 setting, timely NK cell infusion in the early phase of infection could limit SARS-CoV-2 replication and eliminate infected cells. However, in severe cases, the inflammatory milieu might impair the antiviral function of infused NK cells, further exacerbating hypercytokinemia and lung injury. Thus, investigators should carefully evaluate the potential antiviral benefits versus the potential risks of worsening disease status when initiating NK cell therapy. At the time of writing, the results of these trials were either not published or were still in the recruitment phase.
Evidently, NK cells play a critical role in the antiviral response and are closely involved in the COVID-19 pathogenesis. To further improve our knowledge of COVID-19 and innate immunity, especially with regard to NK cells against SARS-CoV-2 infection, future studies need to address several unresolved issues. A study indicated that convalescent patients had a prolonged period of immune dysregulation of T and B cells. However, there are few related studies on NK cells in convalescent individuals. Thus, there is a need for additional studies to determine whether NK cell functions are restored in these individuals. Furthermore, the continuous emergence of variants of SARS-CoV-2 poses a great threat to the efforts of fighting COVID-19 pandemic. Studies have shown that SARS-CoV-2 variants showed reduced neutralization by neutralizing antibodies. While NK cell activation is controlled by the integrated signaling conferred by inhibitory and activating receptors, and it is still unclear about the infection of different SARS-CoV-2 variants on the expression of ligands of NK cell receptors. The NK cells are relatively more enriched in lung tissue than in peripheral blood; however, characterization of tissue-resident NK cells is limited in detail.[63,64] SARS-CoV-2 mainly infects the upper respiratory tract and lungs, and studies concerning NK cells are conducted in peripheral blood. Thus, more researches should focus on the antiviral immune responses of tissue-resident NK cells where viral replication occurs. In addition, during acute SARS-CoV-2 infection, the frequency of myeloid-derived suppressor cells was increased, and studies have shown that myeloid-derived suppressor cell were involved in the functional impairment of NK cells, but the related mechanisms remain unclear. Finally, because inflammation could impair the function of NK cells, studies regarding the application of clinically used anti-inflammatory drugs, including tocilizumab and baricitinib, as well as some TGFβ blockers, on the antiviral function of NK cells, would be of great interest.
Finally, basic studies and clinical trials are needed to further evaluate the optimal doses, suitable time points of NK cell medication, adverse events, and the effectiveness of NK cell–based therapy in the treatment of COVID-19 patients. As of July 18, 2022, more than a total of 12 billion doses of SARS-CoV-2 vaccines had been administered worldwide. After SARS-CoV-2 vaccination, studies have focused on adaptive responses, including humoral and cellular immune responses. Human NK cells also exhibited adaptive features to vaccination or infection. Previously, a study showed that NK cells mediated vaccine-dependent recall responses with antigen specificity and longevity in human volunteers injected with the varicella-zoster virus skin test antigen. Evaluating whether NK cells exhibit adaptive immune responses upon COVID-19 vaccination would be valuable. In addition, vaccinated individuals or convalescent COVID-19 patients may be appropriate candidates to donate NK cells for cell therapy.
In summary, NK cells play an essential role in the anti–SARS-CoV-2 activity and the reduction of lung fibrosis; however, SARS-CoV-2 infection impairs NK cell effector function. Thus, boosting the antiviral potential of NK cells and balancing their deviated immune responses during acute SARS-CoV-2 infection may be a promising strategy for the treatment of this disease.
This work was supported by the National Natural Science Foundation of China (82101837), the National Key R&D Program of China (2020YFC08860900), the Youth Talent Lifting Project (2020-JCJQ-QT-034), and the Beijing Natural Science Foundation (7222171).
All authors conceived the manuscript. Wen-Jing Cao and Jin-Wen Song drafted the manuscript. Fu-Sheng Wang revised the manuscript. All authors approved the final manuscript.
Conflicts of Interest
Editor Note: Fu-Sheng Wang is the editor of Infectious Diseases and Immunity. The article was subject to the journal’s standard procedures, with peer review handled independently by this editor and his research group.
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