SARS-CoV-2-induced IL-6 paralyzes DC function through maturation impairment and immunosuppressive DC3 expansion 2256903

Abstract

Severe COVID-19 is characterized by profound dendritic cell (DC) dysfunction, yet the molecular drivers remain poorly defined. To evaluate DC heterogeneity during COVID-19, we longitudinally immunophenotyped circulating DC subsets in mild and severe cases. We then performed immune correlation analyses across 23 antigen-specific readouts, T cell responses, antibody titers, and inflammatory markers. High-parameter flow cytometry was used to identify drivers of SARS-CoV-2—associated DC dysfunction. Single-cell RNA sequencing (scRNA-seq) profiled peripheral blood DC subsets, and transcriptional analyses evaluated downstream mediators. We demonstrated that IL-6—enriched patient plasma and supernatant from Delta-infected lung epithelial cells reduce CD86 expression on cDC2s and expand the immunosuppressive CD163+ DC3 subset, a phenotype reversible with IL-6 receptor blockade. Single-cell RNA-sequencing revealed the expanded CD163+ DC3 population drives immunosuppression in severe COVID-19 patients. Mechanistically, we implicate the transcription factor C/EBPβ as a critical downstream mediator, based on its disease-associated expression and established role in myeloid cell programming. Overall, this study unveils a novel immune-evasion pathway wherein SARS-CoV-2-induced IL-6 expands immunosuppressive DC3s via C/EBPβ, highlighting IL-6 and C/EBPβ as promising therapeutic targets for ameliorating DC dysfunction in severe COVID-19 and related hyperinflammatory disorders. Hong Kong Collaborative Research Fund (CRF): C7156-20G Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)