Predictive value of NKG2A⁺ NK cell population in diagnosing severe COVID-19 patients

To evaluate the predictive value of NKG2A⁺ natural killer (NK) cells in identifying patients at risk of developing severe COVID-19 and assess the therapeutic potential of NKG2A blockade in restoring NK cell antiviral activity.

The association between NKG2A⁺ NK cells and clinical characteristics was assessed in Omicron-infected patients, and the diagnostic efficacy of NKG2A⁺ NK cell proportions was evaluated using ROC curves. Additionally, NKG2A blockade experiments were conducted in patients infected with the Wuhan strain.

The proportion of NKG2A⁺ NK cells was significantly elevated in patients with severe COVID-19 caused by the Omicron variant, particularly among elderly individuals and those with multiple comorbidities. Integrating NKG2A⁺ NK cell proportions into a laboratory-based model significantly improved the predictive accuracy for severe COVID-19. Patients with NKG2A⁺ NK cell proportions ≥27 % exhibited lower lymphocyte counts and higher levels of NLR, D-dimer, CRP, LDH, and IL-6. Individuals within this high-NKG2A⁺ subgroup also had higher expression of inhibitory receptors (TIM3, TIGIT) and lower expression of activation markers (CD69, CD226, NKG2D), along with increased serum levels of TNF, IL-8, IL-10, and CCL5. Importantly, in Wuhan strain-infected patients, NKG2A blockade significantly restored NK cell activity, as shown by increased expression of activation markers NKG2D, CD69, and CD226, indicating a reversal of NK cell dysfunction.

NKG2A expression contributes to immunosuppression in COVID-19, with NKG2A⁺ NK cells serving as a diagnostic indicator of disease severity. A cut-off value of 27 % NKG2A⁺ NK cells may be clinically relevant for stratifying risk.