Extensive activation, tissue trafficking, turnover and functional impairment of NK cells in COVID-19 patients at disease onset associates with subsequent disease severity

Abstract

The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5–20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage. Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19. NK cells contribute to early phases of virus control and to the regulation of adaptive responses. The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover. We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19. Relevant decreases in CD56brightCD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56dimCD16+KIR+NKG2A+ and “memory” KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules. Impaired cytotoxicity and IFN-γ production were associated with conserved expression of natural cytotoxicity receptors and perforin. Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1brightCXCR4+ inflammatory precursors to mature functional NK cells. Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1brightCXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells. Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration. Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches.

Immunological Analysis of People in Northeast China after SARS-CoV-2 Inactivated Vaccine Injection

“…Although the vaccines were inactivated, they still triggered cellular immune responses after vaccination, including increases of T, Ts, and NK cells. Earlier studies on COVID-19 infections confirmed that virus invasion induces innate immunity [ 19 ]. In studies of mRNA vaccines, BNT162b1 stimulates strong CD4+ T cell and CD8+ T cell responses and strong antibody responses [ 20 ].…”

The immunology of asymptomatic SARS-CoV-2 infection: what are the key questions?

“…The asymptomatic biosignature also involved increased numbers of CD56 hi CD16 − NK cells and a clonal expansion of CD4 + T cell populations. By contrast, symptomatic, acute infection involved a reduction in the number of CD56 hi NK cells and an increased number of CD56 low NK cells 49 . As CD56 hi CD16 − NK cells are the subset associated with cytokine production rather than cytotoxicity, these findings may suggest a regulatory function for NK cell cytokines in asymptomatic disease.…”

NKG2D Natural Killer Cell Receptor—A Short Description and Potential Clinical Applications

“…Limited research on the NK cell derangement during SARS-CoV-2 infection demonstrate that patients suffering from COVID-19 have an increased amount of NK and CD8+T cells with an exhausted phenotype and high expression of the inhibitory receptor, NKG2A [164]. Increased proportions of NK cells expressing activating receptors (NKG2D+, NKG2C+) were found to be protective against the worst outcome, characterized by need for mechanical ventilation [165]. IL-6, that is present in elevated levels in sera of patients with COVID-19 [166], may downreg-ulate NKG2D on NK cells, leading to impairment of NK activity [167].…”