Reduced type I interferon response in plasmacytoid dendritic cells is associated with asthma in school-aged children

Allergic sensitisation and reduced ability to respond to viral infections may contribute to virus-induced wheeze and asthma development in young children. Plasmacytoid dendritic cells (pDC) are rare immune cells that produce type I interferons (IFN-I) and play a key role in orchestrating immune responses against viruses. To further evaluate the function of pDC in children with asthma, we studied a subset of 71 children from the Early Life Lung Function (ELLF) cohort at the age of 7-years. As part of the ELLF study, participants were characterised for atopic sensitisation, viral infection history and lung function testing. pDC responses to a TLR7/8 agonist were assessed in the presence or absence of anti-IgE using an in vitro assay. Responses were evaluated utilising flow cytometry, multiplexed cytokine assays and transcriptional analysis of isolated pDC. pDC responses varied considerably across individuals and those who responded with IFN-I following stimulation showed lower proportion of asthma compared to those who responded with TNF-only. A TNF-only response was associated with increased atopy and reduced upregulation of IFN-associated genes. Anti-IgE stimulation reduced pDC activation and the reduction was associated with baseline expression of the IgE receptor (FceR1). A reduction in a gene module centralised around genes such as TPM2, LILRA4 and CLEC4C was also observed. Together, these findings suggest that pDC responses are variable, associated with asthma and appear influenced by environmental stimuli. This response thus appears to be an important aspect of asthma pathology in children. Overall design: RNASeq of isolated plasmacytoid dendritic cells (pDC). Peripheral blood mononuclear cells from 24 children (age 7 yrs) with or without asthma from the ELLF cohort were stimulated in vitro with R848 (TLR7/8 agonist) with or without pre-incubation of anti-IgE to induce IgE crosslinking. Following stimulation for 16h, pDC were stained and isolated for RNASeq using flow cytometry assisted cell sorting.