Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent

Introduction SARS-CoV-2 is the etiological agent of coronavirus disease 19 (COVID-19) and belongs to the same group of RNA viruses that caused SARS and Middle East respiratory syndrome (MERS) in [...]
BACKGROUND. Coronavirus disease 19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Antiviral immune response is crucial to achieve pathogen clearance; however, in some patients an excessive and aberrant host immune response can lead to an acute respiratory distress syndrome. The comprehension of the mechanisms that regulate pathogen elimination, immunity, and pathology is essential to better characterize disease progression and widen the spectrum of therapeutic options. METHODS. We performed a flow cytometric characterization of immune cell subsets from 30 patients with COVID-19 and correlated these data with clinical outcomes. RESULTS. Patients with COVID-19 showed decreased numbers of circulating T, B, and NK cells and exhibited a skewing of [CD8.sup.+] T cells toward a terminally differentiated/senescent phenotype. In agreement, [CD4.sup.+] T and [CD8.sup.+] T, but also NK cells, displayed reduced antiviral cytokine production capability. Moreover, a reduced cytotoxic potential was identified in patients with COVID-19, particularly in those who required intensive care. The latter group of patients also showed increased serum IL-6 levels that inversely correlated to the frequency of granzyme A-expressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells. CONCLUSION. The association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore antiviral mechanisms. FUNDING. This study was supported by funds from the Department of Experimental and Clinical Medicine of University of Florence (the ex-60% fund and the 'Excellence Departments 2018-2022 Project') derived from Ministero dell'Istruzione, dell'Universita e della Ricerca (Italy).