TCR+CD4-CD8- (double negative) T cells protect from cisplatin-induced renal epithelial cell apoptosis and acute kidney injury
Acute kidney injury (AKI) due to cisplatin is a significant problem that limits its use as an effective chemotherapeutic agent. TCR+CD4-CD8- double negative (DN) T cells constitute major T cell population in human and mouse kidney, express PD1 and protect from ischemic AKI. However, the pathophysiol...
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Veröffentlicht in: | American journal of physiology. Renal physiology 2020-06, Vol.318 (6), p.F1500-F1512 |
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Sprache: | eng |
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Zusammenfassung: | Acute kidney injury (AKI) due to cisplatin is a significant problem that limits its use as an effective chemotherapeutic agent. TCR+CD4-CD8- double negative (DN) T cells constitute major T cell population in human and mouse kidney, express PD1 and protect from ischemic AKI. However, the pathophysiologic roles of DN T cells in cisplatin-induced AKI is unknown. In this study, wild type (WT) mice were treated with cisplatin (30mg/kg) or vehicle and the effect on kidney DN T cell numbers and function were measured. In vitro studies evaluated effects of kidney DN T cells on cisplatin-induced apoptosis and PD ligand 1 (PDL1) in renal epithelial cells. Adoptive transfer studies assessed therapeutic potential of DN T cells during cisplatin-induced AKI. Our results show that kidney DN T cell population increased at 24 hours and declined by 72 hours after cisplatin treatment. Cisplatin treatment increased kidney DN T cell proliferation, apoptosis, CD69 and IL10 expression whereas CD62L, CD44, IL-17A, IFN-γ and TNF-α were downregulated. Cisplatin treatment decreased both PD1 and NK1.1 subsets of kidney DN T cells with pronounced effect on PD1 subset. In vitro kidney DN T cell co-culture decreased cisplatin-induced apoptosis in kidney proximal tubular epithelial cells, increased Bcl-2 and decreased cleaved caspase 3 expression. Cisplatin-induced expression of PD-L1 was reduced in PTECs co-cultured with DN T cells. Adoptive transfer of DN T cells attenuated kidney dysfunction and structural damage from cisplatin-induced AKI. These results demonstrate that kidney DN T cells respond rapidly and play a protective role during cisplatin-induced AKI. |
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ISSN: | 1931-857X 1522-1466 |
DOI: | 10.1152/ajprenal.00033.2020 |