Acute kidney injury (AKI) is associated with a high mortality, morbidity, and increased health care cost. Among the most common etiologies of AKI in both native and transplanted kidneys is ischemia-reperfusion injury (IRI), which has no specific therapy. IRI is also a major process underlying myocardial ischemia and stroke. Mechanisms of early injury and recovery from IRI are complex and remain incompletely understood. IRI involves diverse cell types of the innate and adaptive immune systems, some of which cause damage while others promote injury repair. Efforts to understand the individual and collaborative roles of the different immune cells that reside in the kidney in the steady state or recruited after injury are important for laying the foundation for developing effective strategies o ameliorate renal damage associated with IRI. We have novel data that a fairly newly identified and poorly understood cell type that belong to the TCR+CD4-CD8- double negative (DN) T cell subset, preferentially localizes in large numbers in the normal kidney and changes with age and ischemia. These cells can be anti-inflammatory and genetically modified mice with large quantities of DN T cells are protected from IRI. We hypothesize that DN T cells mediate unique immune functions that are necessary for maintaining local immune responses and renal tubular epithelial cell homeostasis in the steady state, while also protecting from injury and enhancing recovery after IRI. We will begin to test this novel hypothesis through the following specific Aims: In Aim 1, we will test the hypothesis that local DN T cells maintain immune homeostasis by suppression of activated conventional T cells. We will also study effects on renal tubular epithelial cells (RTECs), which make up the bulk of the kidney cells. In Aim 2, we will test the hypothesis that DN T cells directly protect from early injury and accelerate repair after IRI. We will also elucidate mechanisms of action. Results will provide novel information on this newly identified kidney cell and has the potential to harness a novel cell for cell therapy directed to ischemia reperfusion injury. PUBLIC HEALTH RELEVANCE: Immune cells are major players in ischemia reperfusion injury (IRI), a major problem in both native and transplanted kidneys. We plan to investigate the function of a novel T cell subset that resides in significant numbers in normal kidney but wane down after IRI. These studies would lead to better understanding of the kidney immune homeostasis and potentially new therapeutics to decrease injury and inflammation after kidney IRI.