tetano
Editor, Senior Moderator
Front Immunol
. 2026 Oct 20:17:1972608.
doi: 10.3389/fimmu.2026.1972608. eCollection 2026.
Alessandro Frigo 1 2 , Sara Terzoli 1 3 , Paolo Marzano 1 , Nicolò Coianiz 1 , Michela Calvi 1 2 , Lara Orlandi 1 2 , Simone Balin 1 , Valentina Cazzetta 1 , Anna Carletti 1 , Silvia Della Bella 1 2 , Joanna Mikulak 1 , Maciej Tarkowski 4 , Matteo Bonfanti 5 , Paolo Ferrari 5 , Eugenia Ricciardelli 5 , Clelia Peano 5 6 , Agostino Riva 4 7 , Giuseppe Testa 5 8 , Antonio Voza 3 9 , Francesca Calcaterra 1 , Clara Di Vito # 1 2 , Domenico Mavilio # 1 2
Affiliations Expand
Introduction: Vaccination and natural infection with Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) confer immune protection through distinct mechanisms, however, their effects on Natural Killer (NK) cell responses remain poorly understood, particularly in relation to COVID-19 disease severity. NK cells, key mediators of anti-viral immunity, have been implicated in coronavirus disease 2019 (COVID-19) pathogenesis, where severe disease is associated with hyperactivated yet dysfunctional NK-cell states that likely impair viral control and contribute to tissue damage.
Methods: To define how vaccination and infection shape NK-cell biology, we performed longitudinal single-cell RNA sequencing (scRNA-seq) of NK cells from SARS-CoV-2-naïve individuals receiving two doses of the BNT162b2mRNA vaccine. These longitudinal vaccine profiles were integrated with cross-sectional scRNA-seq datasets from unvaccinated patients with acute COVID-19 and from independent convalescent individuals, all enrolled before vaccine introduction.
Results: We identified distinct NK cell transcriptional programs associated with vaccination, acute infection and convalescence, with the most pronounced infection-related alterations observed in the severe form of the disease. These diverging transcriptional signatures correlate with differences in NK-cell subset composition and activation markers between vaccinated and infected individuals.
Conclusions: Taken together, these findings provide a rationale for future studies examining whether vaccine-associated NK-cell transcriptional programs contribute to durable immune protection.
Keywords: COVID-19 severity; NK-cell dysfunction; SARS-CoV-2; natural killer cells; single-cell transcriptomics; vaccination.
. 2026 Oct 20:17:1972608.
doi: 10.3389/fimmu.2026.1972608. eCollection 2026.
Single-cell profiling of dysfunctional NK cells in COVID-19: from immunization to acute infection and beyond
Alessandro Frigo 1 2 , Sara Terzoli 1 3 , Paolo Marzano 1 , Nicolò Coianiz 1 , Michela Calvi 1 2 , Lara Orlandi 1 2 , Simone Balin 1 , Valentina Cazzetta 1 , Anna Carletti 1 , Silvia Della Bella 1 2 , Joanna Mikulak 1 , Maciej Tarkowski 4 , Matteo Bonfanti 5 , Paolo Ferrari 5 , Eugenia Ricciardelli 5 , Clelia Peano 5 6 , Agostino Riva 4 7 , Giuseppe Testa 5 8 , Antonio Voza 3 9 , Francesca Calcaterra 1 , Clara Di Vito # 1 2 , Domenico Mavilio # 1 2
Affiliations Expand
- PMID: 42978614
- PMCID: PMC13727542
- DOI: 10.3389/fimmu.2026.1972608
Abstract
Introduction: Vaccination and natural infection with Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) confer immune protection through distinct mechanisms, however, their effects on Natural Killer (NK) cell responses remain poorly understood, particularly in relation to COVID-19 disease severity. NK cells, key mediators of anti-viral immunity, have been implicated in coronavirus disease 2019 (COVID-19) pathogenesis, where severe disease is associated with hyperactivated yet dysfunctional NK-cell states that likely impair viral control and contribute to tissue damage.
Methods: To define how vaccination and infection shape NK-cell biology, we performed longitudinal single-cell RNA sequencing (scRNA-seq) of NK cells from SARS-CoV-2-naïve individuals receiving two doses of the BNT162b2mRNA vaccine. These longitudinal vaccine profiles were integrated with cross-sectional scRNA-seq datasets from unvaccinated patients with acute COVID-19 and from independent convalescent individuals, all enrolled before vaccine introduction.
Results: We identified distinct NK cell transcriptional programs associated with vaccination, acute infection and convalescence, with the most pronounced infection-related alterations observed in the severe form of the disease. These diverging transcriptional signatures correlate with differences in NK-cell subset composition and activation markers between vaccinated and infected individuals.
Conclusions: Taken together, these findings provide a rationale for future studies examining whether vaccine-associated NK-cell transcriptional programs contribute to durable immune protection.
Keywords: COVID-19 severity; NK-cell dysfunction; SARS-CoV-2; natural killer cells; single-cell transcriptomics; vaccination.