Systemic lupus erythematosus (SLE) afflicts 1 to 2 million Americans, and an estimated 50-60% of these patients develop lupus nephritis (LN) during the first 10 years of disease. The management of LN is still challenging, despite the development of numerous new classes of immune therapeutics. Intrarenal inflammation is a defining feature for LN, relying mainly on the homing of immune cells to the kidney. Therefore, a key unmet need is mechanistic studies that examine specific pathways that govern the homing of immune cells to the kidney. High endothelial venules (HEVs) are specialized veins responsible for the homing of T cells to lymph nodes, and earlier studies from others and us have demonstrated that lymphotoxin (LT) signaling is required for the homeostatic maintenance of functional HEVs. Here, our new data, for the first time, reveal the presence of intrarenal HEVs in the glomeruli and the interstitium in both mouse and human LN kidneys Our overall hypothesis is that the stimulation of LTR+ intrarenal stromal cells by LTa+ Th17 cells drive the formation of intrarenal HEVs, leading to the homing of pro-inflammatory immune cells to the kidney and progression of LN. A series of well-designed experiments will be performed with the novel tools and advanced technology platforms developed in our listed cores to examine the functional role of the interaction between LTR in kidney stromal cells and LTα in Th17 cells in forming HEVs, recruiting inflammatory cells, and advancing LN. We will determine disease outcome in LN after disruption of the interaction between LTα on TH17 cells and LTR on kidney stromal cells (Aim 1 and 2). Aim 3 focuses on our innovative approach to target HEVs for the delivery of first-in-class nano-immune therapeutics (such as anti-CD3 and anti-IL23). These therapeutics will be encapsulated in a polymeric nanoparticle, the surface of which will be coated with MECA-79 mAb, which recognizes HEVs. Our corollary hypothesis is that targeted deliver