Dysregulation of dendritic cells (DCs) contributes to development of Systemic Lupus Erythematosus (SLE) but the mechanisms underpinning this dysregulation are unknown. We recently identified CD244 as immune-regulatory molecule on DCs. CD244 is located in the human SLE susceptibility locus 1q23 and SNPs in CD244 have been identified as risk factors for renal and neuropsychiatric manifestations in SLE. Our preliminary data indicate that SLE patients have decreased CD244 expression on their DCs.  We found that inhibition of CD244 signaling in mouse DCs markedly increased their pro-inflammatory cytokine production and T cell activating capacity. Moreover, reduction of CD244 or its adaptor molecules significantly increased susceptibility to SLE in various spontaneous and inducible mouse models. Given the homology in mouse and human CD244/adaptor molecule sequences and expression pattern, we hypothesize that altered CD244 signaling in DCs contributes to the proinflammatory environment and the immune-dysregulation observed in SLE and can therefore be used as disease biomarker and exploited for therapeutic targeting.  To test the hypothesis we will assess CD244 and adaptor molecule expression in DCs from SLE patients, and determine the effect of pharmacologic targeting of CD244 and its pathway on human DC function in vitro and SLE development in in vivo mouse models.