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

J Clin Invest. 2020 Sep 1;130(9):4694-4703. doi: 10.1172/JCI138554.


BACKGROUNDCoronavirus 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.METHODSWe performed a flow cytometric characterization of immune cell subsets from 30 patients with COVID-19 and correlated these data with clinical outcomes.RESULTSPatients with COVID-19 showed decreased numbers of circulating T, B, and NK cells and exhibited a skewing of CD8+ T cells toward a terminally differentiated/senescent phenotype. In agreement, CD4+ T and CD8+ 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.CONCLUSIONThe association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore antiviral mechanisms.FUNDINGThis 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'Università e della Ricerca (Italy).

Keywords: Cellular immune response; Cytokines; Immunology; Infectious disease; NK cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • B-Lymphocytes / immunology
  • Betacoronavirus*
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • COVID-19
  • Coronavirus Infections / blood
  • Coronavirus Infections / epidemiology
  • Coronavirus Infections / immunology*
  • Critical Care
  • Cytokines / blood
  • Cytokines / immunology
  • Cytotoxicity, Immunologic*
  • Female
  • Granzymes / blood
  • Granzymes / immunology
  • Humans
  • Interleukin-6 / blood
  • Interleukin-6 / immunology*
  • Killer Cells, Natural / immunology
  • Male
  • Middle Aged
  • Models, Immunological
  • Pandemics
  • Pneumonia, Viral / blood
  • Pneumonia, Viral / epidemiology
  • Pneumonia, Viral / immunology*
  • SARS-CoV-2


  • Cytokines
  • IL6 protein, human
  • Interleukin-6
  • Granzymes
  • GZMA protein, human