The role of adaptive NK cells in the control of SARS-CoV-2 infection

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Natural killer (NK) cells are part of the first line of defense against acute viral infections. Recently, a novel type of virus-specific adaptive NK cell was identified that expands during acute cytomegalovirus (CMV) infection and is generally hypersensitive to stimulation by IgG antibodies leading to highly efficient and rapid antibody-mediated cellular cytotoxicity (ADCC). A hallmark of these adaptive (also known as memory) NK cells is the expression of the stimulatory receptor NKG2C, which is specific for the Human Leucocyte Antigen E (HLA-E). We have recently shown that adaptive NKG2C+ NK cells are stably maintained as large clonal expansions in 30-40% of HCMV+ cases. Furthermore, we have shown that the size of these expansions correlates with the coexpression of KIR2DL receptors, which are inhibitory receptors for HLA-C and members of the highly polymorphic KIR family. Due to their high ADCC potential, adaptive NK cells could play a critical role in SARS-CoV-2 infection, which is often associated with strong IgG antibody responses. Indeed, it was recently shown that patients with severe disease exhibited increased presence of adaptive NK cells in the circulation. Importantly, in contrast to conventional NK cells, adaptive NK cells can persist for many years and thus have the potential to contribute to long-term protection against re-infection. In this project, we would like to find out how adaptive NKG2C+ NK cells influence the outcome of SARS-CoV-2 infection. We will address this in samples from convalescent COVID-19 patients (MU) as well as in a primate model of Covid-19 (LW). The Düsseldorf team has already collected samples and clinical data on >130 SARS-CoV-2 cases and would like to correlate the relevant clinical parameters such as disease severity, virus load, SARS-CoV-2-specific IgM and IgG titer, and CMV status with the presence of adaptive NK cells by multicolor flow cytometry. Furthermore, based on the recent observation that the SARS-CoV-2 spike protein SP1 leads to upregulation of HLA-E in lung epithelial cells, we will explore in vitro if this mechanism leads to stimulation and expansion of adaptive NK cells via the HLA-E/NKG2C axis. The Göttingen team at the German Primate Center (DPZ) could already demonstrate the presence of similar CMV-associated expansions in macaques on the basis of newly-developed mAbs specific for macaque NKG2C and KIR. We would thus like to study the contribution of adaptive NK cells in the acute phase of SARS-CoV-2 infection, employing experimentally infected rhesus macaques. The analysis of blood samples as well as tissue sections will give us the unique opportunity to monitor the distribution and functional role of adaptive NK cells in this primate model. If adaptive NK cells are indeed involved in control of SARS-CoV-2 infection, this innate immune cell type, which can be easily expanded in vitro, could provide a highly interesting novel option for allogeneic cellular therapy of COVID-19 patients.