Age-dependent NK cell dysfunctions in severe COVID-19 patients

Abstract

Natural Killer (NK) cells are key innate effectors of antiviral immune response, and their activity changes in ageing and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we investigated the age-related changes of NK cell phenotype and function during SARS-CoV-2 infection, by comparing adult and elderly patients both requiring mechanical ventilation. Adult patients had a reduced number of total NK cells, while elderly showed a peculiar skewing of NK cell subsets towards the CD56lowCD16high and CD56neg phenotypes, expressing activation markers and check-point inhibitory receptors. Although NK cell degranulation ability is significantly compromised in both cohorts, IFN-γ production is impaired only in adult patients in a TGF-β−dependent manner. This inhibitory effect was associated with a shorter hospitalization time of adult patients suggesting a role for TGF-β in preventing an excessive NK cell activation and systemic inflammation. Our data highlight an age-dependent role of NK cells in shaping SARS-CoV-2 infection toward a pathophysiological evolution.

Impact of immunosenescence and inflammaging on the effects of immune checkpoint inhibitors

“… 65 Immunosenescence can lead to age-related changes in NK cell functions, characterized by reduced abilities to release cytokines and induce apoptosis in tumor cells. 65 For instance, senescent NK cells may bind to IL-2, but they release lower levels of IFN-γ 66 and age-related NK cell dysfunction can reduce perforin and granzyme expression. 67 Therefore, NK cell cytotoxicity is reduced by cellular senescence, which is associated with an increased risk of developing cancer.…”

Impact of aging on immunity in the context of COVID-19, HIV, and tuberculosis

“…CD56 bright CD16 + are lytic while CD56 bright CD16 - are cytokine producing ( 41 , 42 ). Elderly individuals have NK cell subsets that are CD56 low CD16 high and CD56 - , and express check-point inhibitory receptors and activation marker phenotypes ( 43 ). Above 50 years of age increasing integrin α4β7 and decreasing C-C chemokine receptor type 7 (CCR7) has been observed ( 44 ).…”

“…NK cell polarization is also affected in severe COVID-19 and age, particularly memory-like NK2.1 cells and related produced cytokines are associated with disease severity in COVID-19 ( 45 ). Specifically, IFN-γ due to an early excessive NK cell activation is involved in inflammatory response with a poor prognosis in elderly COVID-19 patients and TGF-β is associated with a shorter hospitalization time of adult patients suggesting a role for TGF-β in preventing an excessive NK cell activation and systemic inflammation ( 43 ). Overall, the changes to the innate immune system in older COVID-19 patients can contribute to a greater risk for cytokine storm, due to the proinflammatory environment and reduction in pathogens clearance making them more vulnerable to SARS-CoV-2, and eventually lead to severe cases, more complications, or deaths ( 10 , 11 , 99 ).…”

NK cell subsets and dysfunction during viral infection: a new avenue for therapeutics?

“…In the context of COVID-19 infection, TGF-β signaling has been associated with a stark reduction in NK cell effector functions, with patient serum having been found to inhibit NK cell cytotoxicity in a TGF-β dependent manner ( 194 ). Similarly, impairments in IFN- γ production appear to occur in a TGF-β dependent manner ( 211 ). This suggests that TGF-β signaling contributes significantly to NK cell dysregulation and exhaustion during COVID-19.…”