Three discovery-driven components will shed light on mechanisms underlying SLE, and suggest novel therapeutic approaches. They are built around recruitment of a well-characterised SLE patient cohort to be studied before and after treatment, which in itself should replicate a CD8 T cell prognostic signature that we have previously described, allowing its adoption as a prognostic biomarker in the clinic 1. It will examine in detail the role played by interferon in determining long-term outcome through its effect on T cell exhaustion processes we have found underly prognostic signatures. This might allow induction of exhaustion in defined patients through co-stimulation or IFN blockade. 2. We recently discovered the follicular regulatory T cell (TFR), that seems likely to control autoimmunity. We will define the role played by TFR in SLE to assist with our understanding of disease pathogenesis using single cell transcriptomics (SCT) and transgenic approaches, and explore TFR as biomarkers or therapeutic targets. 3. We have shown inflammatory plasma cells (PCI) are major autoantibody producers in SLE, are likely to contribute to both systemic and local disease. We will explore the pathological importance of PCI, and seek therapeutic approaches to them, with SCT and a novel renal transplantation approach.