Systemic lupus erythematosus afflicts 1 to 2 million Americans and is associated with significant morbidity and mortality. While wiser use of immunosuppressive drugs and prompt treatment of complications have improved the overall survival and quality of life, we still lack specific drugs, full understanding of the involved pathogenic processes and valuable disease biomarkers. In addition, our understanding of local, organ-specific mechanisms involved in the execution of tissue injury is limited. An expanded population of T cells missing CD4 and CD8 from the surface (double negative T cells) in the peripheral blood of patients with systemic lupus erythematosus, helps autologous B cells to produce immunoglobulin and dsDNA antibodies, produces the proinflammatory interleukin 17 and invades tissues to cause inflammation. This application proposes the use of state-of-the-art new technologies including spectral cytometry, single cell RNA sequencing and series of novel engineered mice to study the diversity of the double negative T cell population in the peripheral blood and kidneys of lupus-prone mice and people with systemic lupus erythematosus and understand how an inflammatory environment contributes to their generation. In parallel, experiments are proposed to understand how inflammatory cytokines act on kidney resident cells to enable the establishment of inflammation. The proposed experiments will inform the development of approaches to suppress the generation of pathogenic double negative T cells and prevent the establishment of tissue inflammation.