Academic Journal
Programmed cell death protein 1 (PD-1) regulates metabolic activity of regulatory T cells in ischemia-induced acute kidney injury.
| Τίτλος: | Programmed cell death protein 1 (PD-1) regulates metabolic activity of regulatory T cells in ischemia-induced acute kidney injury. |
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| Συγγραφείς: | Pelletier OB; Center for Immunity, Inflammation and Regenerative Medicine, Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA, United States., Dogan M; Center for Immunity, Inflammation and Regenerative Medicine, Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA, United States., O'Neill C; Center for Immunity, Inflammation and Regenerative Medicine, Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA, United States., Sabapathy V; Center for Immunity, Inflammation and Regenerative Medicine, Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA, United States., Portilla D; Center for Immunity, Inflammation and Regenerative Medicine, Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA, United States., Sharma R; Center for Immunity, Inflammation and Regenerative Medicine, Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA, United States. |
| Πηγή: | Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2026 Oct 01; Vol. 215 (10). |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Association of Immunologists Country of Publication: England NLM ID: 2985117R Publication Model: Print Cited Medium: Internet ISSN: 1550-6606 (Electronic) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Bethesda, MD : American Association of Immunologists Original Publication: Baltimore : Williams & Wilkins, c1950- |
| Ιατρικοί όροι (MeSH): | T-Lymphocytes, Regulatory*/immunology , T-Lymphocytes, Regulatory*/metabolism , Acute Kidney Injury*/metabolism , Acute Kidney Injury*/etiology , Acute Kidney Injury*/immunology , Acute Kidney Injury*/pathology , Programmed Cell Death 1 Receptor*/genetics , Programmed Cell Death 1 Receptor*/metabolism , Reperfusion Injury*/immunology , Reperfusion Injury*/metabolism , Reperfusion Injury*/complications, Mitochondria/metabolism ; Kidney/pathology ; Kidney/immunology ; Animals ; Mice ; Mice, Knockout ; Oxidative Phosphorylation ; Mice, Inbred C57BL ; Male |
| Περίληψη: | Immune checkpoint inhibitor (ICPI) therapy, targeting Programmed cell death protein 1 (PD-1) and its ligands PD-L1 and PD-L2, have revolutionized cancer care. 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-deficient 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-deficient Tregs and underscore the importance of PD-1 in Treg-mediated protection against AKI with implications for ICPI-related nephropathy. (© The Author(s) 2026. Published by Oxford University Press on behalf of The American Association of Immunologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) |
| Grant Information: | R01DK104963 United States DK NIDDK NIH HHS; R01DK105833 United States DK NIDDK NIH HHS; 13-03 Virginia Catalyst; 16-04 Virginia Catalyst; 3-SRA-2021-1005-S-B Juvenile Diabetes Research Foundation; 3-SRA-2025-1733-S-B Juvenile Diabetes Research Foundation; 5TL1DK132771 IGNITE KUH Fellowships |
| Contributed Indexing: | Keywords: AKI; PD-1; Treg; metabolism; mitochondria |
| Substance Nomenclature: | 0 (Programmed Cell Death 1 Receptor) 0 (Pdcd1 protein, mouse) |
| Entry Date(s): | Date Created: 20261007 Date Completed: 20261007 Latest Revision: 20261007 |
| Update Code: | 20261008 |
| DOI: | 10.1093/jimmun/vkag234 |
| PMID: | 42842323 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1550-6606 |
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| DOI: | 10.1093/jimmun/vkag234 |