Single cell variability in pro-inflammatory and antiviral gene responses in dendritic cells

Abstract

Abstract Type I interferons (IFNs) can have both protective and deleterious effects in chronic infection and autoimmune disease. Cellular responses to type I IFNs are mediated by IFN-stimulated genes (ISGs), are cell type-dependent, and likely cell specific. Varying responses of individual cells to immune signals, such as type I IFNs, may be critical in orchestrating context and microenvironment appropriate immune responses. Simulations of an agent-based mathematical model of viral infection suggested that within each cell, the levels of pro-inflammatory ISGs induced by STAT dimers and the antiviral ISGs induced by the ISGF-3 heterotrimer can show low correlation. We used RNAseq to study global single-cell correlation of ISG groups in human peripheral blood CD1c+ dendritic cells infected with an influenza A H1N1 virus. Consonant with the simulations, distinct groups of ISGs were identified that showed high levels of single cell expression correlation within, but low to negative correlations across ISG subgroups. Using multiple probe FISH we find low single cell correlation of the pro-inflammatory ISG IL6 and the antiviral ISG RIG-I induction in cells stimulated with type I IFN. The single cell correlations in the induction of the two genes were 0.56, 0.55 and 0.19 in human peripheral blood plasmacytoid dendritic cells, monocytes, and monocyte-derived dendritic cells respectively. The generation of uncorrelated pro-inflammatory and antiviral ISG single cell responses within a dendritic cell population can increase the breadth of the immune response to noxious stimuli.