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However, ICPI is linked to immune-related adverse events, including nephropathy manifesting as acute kidney injury (AKI), a rapid decline in kidney function, often progressing to renal failure. Regulatory T cells (Tregs) could mitigate AKI, caused by ischemia-reperfusion injury (IRI). Treg stability and function rely on cellular metabolism, with a distinct preference for oxidative phosphorylation (OXPHOS) over glycolysis. Although PD-1 is known to regulate metabolism of CD8 T cells, its role in controlling OXPHOS in Tregs remains underexplored. We demonstrate that PD-1 knockout (KO) mice have worse renal function after IRI when compared to wild-type mice. PD-1\u2013deficient Tregs lose their protective ability against AKI despite retaining in vitro suppressive activity and Foxp3 expression. Transcriptomic analysis reveals altered expression of genes linked to function, proliferation, and mitochondrial metabolism in PD-1 KO Tregs as compared to wild-type Tregs. PD-1 KO Tregs exhibit reduced mitochondrial mass, membrane potential, biogenesis, and dynamics, leading to impaired mitochondrial fitness and trends for reduced expression of fatty acid transporters CD36 and Cpt1a and Glut1. Loss of PD-1 expression or antibody-mediated blockade of PD-1 attenuated OXPHOS and expression of genes related to mitochondrial metabolism in Tregs. These metabolic defects may stem from morphological alterations in mitochondria, highlighting the critical role of PD-1 in Treg-mediated nephroprotection. Our findings reveal the metabolic vulnerability of PD-1\u2013deficient Tregs and underscore the importance of PD-1 in Treg-mediated protection against AKI with implications for ICPI-related nephropathy.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag234","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:09:52Z","timestamp":1791385792000},"source":"Crossref","is-referenced-by-count":0,"title":["Programmed cell death protein 1 (PD-1) regulates metabolic activity of regulatory T cells in ischemia-induced acute kidney injury"],"prefix":"10.1093","volume":"215","author":[{"given":"Oliver B","family":"Pelletier","sequence":"first","affiliation":[{"name":"Center for Immunity, Inflammation and Regenerative Medicine, Division of Nephrology, Department of Medicine, University of Virginia , Charlottesville, VA,","place":["United 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