Repression of the H3K4 demethylase Jarid1b leads to activation of RSV-infected dendritic cells (68.18)

Abstract

Abstract Respiratory syncytial virus (RSV) is a common pathogen in children, with nearly all children being infected before the age of 2. Severe infection requiring hospitalization has been linked to the development of asthma later in life due to an improper Th2 skewing of the immune response. Dendritic cells (DCs) are key cells involved in presenting antigen to T cells and polarizing the T cell response. It has been reported that RSV interferes with the initiation of the adaptive immune response by inhibiting the production of type I interferons (IFN), including IFNβ, thus leading to a Th2 environment in the lungs. The mechanism by which this occurs is not fully understood. Epigenetic modulation of gene transcription has been shown to be important in regulating inflammatory pathways. We found that bone marrow derived DCs (BMDCs) infected with the RSV clinical isolate A2001/2-20 upregulated expression of Jarid1b, an H3K4 demethylase. Jarid1b has been described as a transcriptional repressor in cancer cells. We therefore hypothesized that Jarid1b plays a role in suppressing inflammatory genes in RSV infected DCs. We used siRNA to downregulate Jarid1b in BMDCs. Loss of Jarid1b led to a 10-fold increase in IFNβ compared to cells transfected with non-specific siRNA, as well as an increase in IL-6 and TNF-α. DC phenotype was unaffected as determined by flow cytometry. Investigations into the role that Jarid1b-induced DC regulation has in directing the T cell response are ongoing.