Cytokines produced by lymphocytes of the innate and adaptive immune system are central regulators of the immune response in homeostasis and immune-mediated diseases. Recent studies have shown that specialized subsets of “innate-like” T cells that display features of both innate and adaptive immunity, as well as different innate lymphocyte populations reside in the kidney, where they contribute to production of cytokines and regulation of the local immune response. However, the contribution of these innate and innate-like lymphocyte populations to kidney injury and repair in immune-mediated glomerular diseases is still incompletely understood. In the proposed project we will investigate the role of innate-like T cell subsets (focusing on MAIT cells) and innate lymphocyte populations (focusing on NK cells) in immune-mediated glomerular diseases. In a hypothesis based approach, we will first use an experimental mouse model of glomerulonephritis to study the function of kidney-resident NK cells and MAIT cells in glomerular inflammation. These studies will be complemented by a systems biology approach, in which we will perform a high dimensional analysis of the molecular interactions of innate and innate-like lymphocytes with renal parenchymal cells in the healthy human kidney and in renal biopsies of glomerulonephritis patients. Selected interaction pathways identified in these unbiased analyses of human kidney samples will then be subjected to functional testing in in vitro co-culture systems with lymphocytes and renal epithelial cells and in the glomerulonephritis model. In summary, our studies will elucidate the role of innate and innate-like lymphocyte subsets in the renal immune response and will thereby pave the way for targeted treatment approaches in patients with immune-mediated glomerular diseases.