Identification of human immune cell subtypes most responsive to IL-1β-induced inflammatory signaling using mass cytometry

IL-1 beta is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1 beta blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4(+) T cells and CD4(-)CD8(low/-)CD161(+) T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1 beta. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-kappa B and was also seen in other subsets, including CD11c(+) myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16(-)CD56(bright)CD161(-) and CD16(-)CD56(dim)CD161(+)), and lineage(-) (Lin(-)) cells expressing CD161 and CD25. IL-1 beta also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-kappa B in most of these immune cell subsets. Prolonged IL-1 beta stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1 beta-induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by anakinra raise the possibility that assays measuring NF-kappa B phosphorylation in response to IL-1 beta in CCR6(+) T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1 beta-neutralizing therapies.