Systemic Lupus Erythematosus (SLE) is perpetuated by elevated IFN-I levels and associated immunopathology. Plasmacytoid dendritic cells (pDCs), which are specialized to produce IFN-I, are continuously activated by self nucleic acids and play a pivotal role in disease progression. Therefore, silencing PDC IFN-I production represents an attractive strategy to ameliorate lupus. We have characterized a PDC “exhaustion” state during which PDC IFN-I production becomes dramatically silenced despite the continuous presence of stimuli during chronic viral infection (Zuniga et al CH&M 2008; Macal et al CH&M 2012). Using a genome wide analysis, we have identified the transcriptional signature of exhausted pDCs and we propose to manipulate selected PDC exhaustion genes (e.g. those oppositely regulated in SLE) to interrupt their IFN-I production and break the pathogenic loop in lupus-prone mice. The short-term impact of our studies will be the identification of molecular determinants that can brake the pathogenic IFN-I cycle in a mouse model of SLE. The unique translational design (from virus infection to lupus) that we propose will provide invaluable insight into PDC manipulation. The long-term impact of our studies will be to translate the new knowledge on IFN-I regulation into novel therapeutic modalities in SLE.