NK cells in COVID-19-from disease to vaccination

Natural killer cells participate in the host innate immune response to viral infection. Conversely, natural killer cell dysfunction and hyperactivation can contribute to tissue damage and immunopathology. Here, we review recent studies with respect to natural killer cell activity during infection with SARS-CoV-2. Discussed are initial reports of patients hospitalized with COVID-19, which revealed prompt natural killer cell activation during the acute disease state. Another hallmark of COVID-19, early on observed, was a decrease in numbers of natural killer cells in the circulation. Data from patients with acute SARS-CoV-2 infection as well as from in vitro models demonstrated strong anti-SARS-CoV-2 activity by natural killer cells, likely through direct cytotoxicity as well as indirectly by secreting cytokines. Additionally, we describe the molecular mechanisms underlying natural killer cell recognition of SARS-CoV-2-infected cells, which involve triggering of multiple activating receptors, including NKG2D, as well as loss of inhibition through NKG2A. Discussed is also the ability of natural killer cells to respond to SARS-CoV-2 infection via antibody-dependent cellular cytotoxicity. With respect to natural killer cells in the pathogenesis of COVID-19, we review studies demonstrating how hyperactivation and misdirected NK cell responses could contribute to disease course. Finally, while knowledge is still rather limited, we discuss current insights suggesting a contribution of an early natural killer cell activation response in the generation of immunity against SARS-CoV-2 following vaccination with anti-SARS-CoV-2 mRNA vaccines.