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

Mazzoni, Alessio; Salvati, Lorenzo; Maggi, Laura; Capone, Manuela; Vanni, Anna; Spinicci, Michele; Mencarini, Jessica; Caporale, Roberto; Peruzzi, Benedetta; Antonelli, Alberto; Trotta, Michele; Zammarchi, Lorenzo; Ciani, Luca; Gori, Leonardo; Lazzeri, Chiara; Matucci, Andrea; Vultaggio, Alessandra; Rossi, Oliviero; Almerigogna, Fabio; Parronchi, Paola; Fontanari, Paolo; Lavorini, Federico; Peris, Adriano; Rossolini, Gian Maria; Bartoloni, Alessandro; Romagnani, Sergio; Liotta, Francesco; Annunziato, Francesco; Cosmi, Lorenzo

BACKGROUND Coronavirus disease 19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Anti-viral 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 cells subsets from 30 COVID-19 patients and correlated these data with clinical outcomes. RESULTS COVID-19 patients showed decreased numbers of circulating T, B and NK cells, and exhibited a skewing of CD8+ T cells towards a terminally differentiated/senescent phenotype. In agreement, T CD4+, T CD8+ but also NK cells displayed reduced anti-viral cytokine production capability. Moreover, a reduced cytotoxic potential was identified in COVID-19 patients, particularly in those that required intensive care. The latter group of patients showed also increased serum IL-6 levels, that correlated to the frequency of granzyme-expressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells. CONCLUSION In conclusion, the association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore anti-viral mechanisms. FUNDING This study was supported by funds of Dept. of Experimental and Clinical Medicine of University of Florence (ex-60%) derived from Ministero dell'Istruzione, dell'Università e della Ricerca (Italy).