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

IL-1β is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1β 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-1β. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c⁺ myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16^-CD56^brightCD161^- and CD16^-CD56^dimCD161⁺), and lineage^- (Lin^-) cells expressing CD161 and CD25. IL-1β also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1β 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-1β-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-κB phosphorylation in response to IL-1β in CCR6⁺ T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1β-neutralizing therapies.