tetano
Editor, Senior Moderator
Scand J Immunol
. 2026 Apr;103(4):e70115.
doi: 10.1111/sji.70115.
Decoding NK Cell Subset Dysregulation in SARS-CoV-2 Infection: Phenotypic, Functional, and Transcriptomic Insights Into COVID-19 Pathogenesis
Marlyn D Sepúlveda[SUP] 1 [/SUP], Walter D Cardona Maya[SUP] 2 [/SUP], Wildeman Zapata-Builes[SUP] 3 [/SUP], Paula A Velilla[SUP] 1 [/SUP]
Affiliations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection significantly affects innate immune responses, particularly those of natural killer (NK) cells, which play an important role in antiviral defence. This review combines phenotypic, functional, and transcriptomic findings to explain the disruption of NK cell subsets in COVID-19. Flow cytometry studies have shown generalised lymphopenia and a significant reduction in the CD56bright and CD56[SUP]dim[/SUP]CD16[SUP]+[/SUP] subsets. This change is linked to an increase in the CD56[SUP]dim[/SUP]CD16[SUP]-[/SUP] and CD56[SUP]-[/SUP]CD16[SUP]+[/SUP] populations, which correlate with disease severity. At the molecular level, there is an imbalance between activating and inhibitory receptors. This includes increases in NKG2A, PD-1, and LAG-3, along with decreases in NKp30, NKp46, and NKG2D. These findings are consistent with an exhausted phenotype and weakened cytotoxicity. Single-cell RNA sequencing (scRNA-seq) studies have identified an increase in proliferative, cytotoxic, and platelet-associated CD56[SUP]dim[/SUP] NK subpopulations in severe cases and a reduction of CD56[SUP]bright[/SUP] cells. Transcriptomic profiling showed that upregulation of interferon-stimulated genes (ISGs) and inflammatory pathways driven by STAT1/3, NF-κB activation, and transforming growth factor-beta (TGF-β) signalling suppresses NK effector functions. Collectively, these findings suggest a model in which progressive NK cell dysfunction may be associated with the immunopathogenesis of COVID-19. The integration of multi-omic and phenotypic approaches provides a comprehensive view of NK cell responses to SARS-CoV-2 and suggests potential biomarkers and therapeutic targets to restore NK cell antiviral activity.
Keywords: NK cell subsets; NK cells; SARS‐CoV‐2; bulk RNAseq; scRNAseq.
. 2026 Apr;103(4):e70115.
doi: 10.1111/sji.70115.
Decoding NK Cell Subset Dysregulation in SARS-CoV-2 Infection: Phenotypic, Functional, and Transcriptomic Insights Into COVID-19 Pathogenesis
Marlyn D Sepúlveda[SUP] 1 [/SUP], Walter D Cardona Maya[SUP] 2 [/SUP], Wildeman Zapata-Builes[SUP] 3 [/SUP], Paula A Velilla[SUP] 1 [/SUP]
Affiliations
- PMID: 41981866
- DOI: 10.1111/sji.70115
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection significantly affects innate immune responses, particularly those of natural killer (NK) cells, which play an important role in antiviral defence. This review combines phenotypic, functional, and transcriptomic findings to explain the disruption of NK cell subsets in COVID-19. Flow cytometry studies have shown generalised lymphopenia and a significant reduction in the CD56bright and CD56[SUP]dim[/SUP]CD16[SUP]+[/SUP] subsets. This change is linked to an increase in the CD56[SUP]dim[/SUP]CD16[SUP]-[/SUP] and CD56[SUP]-[/SUP]CD16[SUP]+[/SUP] populations, which correlate with disease severity. At the molecular level, there is an imbalance between activating and inhibitory receptors. This includes increases in NKG2A, PD-1, and LAG-3, along with decreases in NKp30, NKp46, and NKG2D. These findings are consistent with an exhausted phenotype and weakened cytotoxicity. Single-cell RNA sequencing (scRNA-seq) studies have identified an increase in proliferative, cytotoxic, and platelet-associated CD56[SUP]dim[/SUP] NK subpopulations in severe cases and a reduction of CD56[SUP]bright[/SUP] cells. Transcriptomic profiling showed that upregulation of interferon-stimulated genes (ISGs) and inflammatory pathways driven by STAT1/3, NF-κB activation, and transforming growth factor-beta (TGF-β) signalling suppresses NK effector functions. Collectively, these findings suggest a model in which progressive NK cell dysfunction may be associated with the immunopathogenesis of COVID-19. The integration of multi-omic and phenotypic approaches provides a comprehensive view of NK cell responses to SARS-CoV-2 and suggests potential biomarkers and therapeutic targets to restore NK cell antiviral activity.
Keywords: NK cell subsets; NK cells; SARS‐CoV‐2; bulk RNAseq; scRNAseq.