Dendritic cell activation through ligation of pattern recognition receptors leading to full functional maturation causes induction of CD8 T cell immunity instead of tolerance through increased delivery of co-stimulatory signals. Here we investigate whether a prototypic organ-resident antigen-presenting cells, i.e. liver sinusoidal endothelial cells (LSEC), also switch from tolerogenic to immunogenic CD8 T cell activation upon such activation. We demonstrate by gene expression analysis that LSEC expressed numerous pattern recognition receptors that attributed sentinel function, but ligand-induced activation of these receptors was not sufficient to overcome tolerance induction of CD8 T cells. However, viral infection caused functional maturation of antigen-presenting LSEC and was sufficient to promote antigen-specific differentiation into fully functional effector CD8 T cells in the absence of dendritic cells. Thus, we identify a novel principle of inducing CD8 T cell immunity by virally infected organ-resident antigen-presenting cells employing distinct mechanisms compared to dendritic cells. Overall design: Transcriptional profiles of untreated liver sinusoidal endothelial cells (LSEC) and LSEC, stimulated with either LPS (100ng/ml) or infected with MCMV-GFP (MOI=0.1) were compared on Illumina Mouse WG-6 BeadChip microarray platform. All samples represent biological replicates and were processed separately throughout the experiment.