Title: A Novel Inflammatory Dendritic Cell in Lupus Nephritis Abstract/Project Summary: Dendritic cells (DC) are important immune regulators that play a pivotal role in autoimmunity by either promoting tolerance or promoting self-reactive immune responses. Accordingly, aberrant activation of DC is implicated in the pathogenesis of most autoimmune diseases. We have identified a new subset of inflammatory dendritic cells (infDC) that are found in abundance in the kidneys of patients with lupus nephritis (LN), the most common serious organ complication of systemic lupus erythematosus (SLE). These infDC are localized mainly to the periglomerular region of human LN kidney during active disease, a compartment of the kidney not well studied in LN. Of particular relevance is that is that in human LN kidneys infDC appear to spatially associate with T cells that transcriptionally resemble Th17 cells. This is significant because of the known relevance of Th17 pathways in LN. Taken together we suggest that the periglomerular co-localization of infDC and Th17 cells are consequential in initiating and exacerbating LN. The central hypothesis of this proposal is that infDC are the master initiators and drivers of local inflammatory kidney injury by activation of Th17 cells during LN, and that characterizing these relationships will improve our understanding of LN pathogenesis and lead to new therapeutic opportunities. This hypothesis will be tested in three aims. In Aim 1, periglomerular infDC and T cell expression patterns will be characterized in human LN to determine expression heterogeneity and correlation with disease activity. The second aim tests the hypothesis that infDC are damaging to the kidney during LN by demonstrating that depleting or increasing infDC attenuates or exacerbates intra-renal inflammation during LN. The third aim will test the hypothesis that infDC initiate an inflammatory pathway by supporting a cytokine milieu that differentiates intra-renal naïve T cells to a Th17 phenotype. This proposal is significant as it will establish the mechanisms by which this novel population of InfDC initiates and maintains tissue injury during LN flare, and in turn will identify the relevant inflammatory pathways that can be targeted to attenuate flare and improve outcomes in LN. In summary, this work should provide new insights into how renal inflammation is initiated during LN flare by describing how periglomerular InfDC drive the local immune response in the kidney. Thus our investigations are expected to yield a major advance in understanding the basic biology behind kidney-specific autoimmunity during human LN.