Mechanism of combinatorial cytokine effects on dendritic cell state (P1200)

Abstract

Abstract The effects of cytokine microenvironment on cellular response state are potentially important and relatively unexplored in the immune system. We focus on elucidating the combinatorial effects of extracellular signaling in the dendritic cells (Dc) and the mechanisms responsible for decoding these signals. Newcastle disease virus infected human dendritic cells in culture secret 21 extracellular factors for which they express receptors. Previously we showed that paracrine cytokines involving more than type I interferon released by virus-infected human Dcs dictate an antiviral maturation state of naïve Dcs. Microarray studies identified 260 genes that are differentially regulated (p≤0.05; >2-fold) by infected Dc supernatant compared to cells treated with IFNβ alone. Combinatorial cytokine studies indicate that IFNβ and TNFα are major factors that together are responsible for stimulating this state in Dcs. Linear regression modeling of microarray data identified 727 synergistically regulated genes and gene set enrichment analysis implicated STAT-5, STAT-6 and IRF-1. The combinatorial activation of these transcription factors was confirmed by imaging flow cytometry. These results suggest that the cytokine microenvironment generate Dc response states via the activation of combinatorial-responsive transcription factors. Combinatorial regulation mechanisms may provide the ability for localized control of the activation state of immune cells to spatially tune the response to infection.