Beta cell extracellular vesicle PD-L1 as a novel regulator of CD8

• Tác giả: Daniel T Cater, Andre G De Oliveira, Decio L Eizirik, Carmella Evans-Molina, Raghavendra G Mirmira, Jon D Piganelli, Chaitra Rao, Saptarshi Roy, Emily K Sims, Jerry Xu
• Ngôn ngữ: eng
• Ký hiệu phân loại: 615.8043 Specific therapies and kinds of therapies
• Thông tin xuất bản: Germany : Diabetologia , 2025
• Bộ sưu tập: NCBI
• ID: 677583

Tóm tắt

AIMS/HYPOTHESIS: Surviving beta cells in type 1 diabetes respond to inflammation by upregulating programmed death-ligand 1 (PD-L1) to engage immune cell programmed death protein 1 (PD-1) and limit destruction by self-reactive immune cells. Extracellular vesicles (EVs) and their cargo can serve as biomarkers of beta cell health and contribute to islet intercellular communication. We hypothesised that the inflammatory milieu of type 1 diabetes increases PD-L1 in beta cell EV cargo and that EV PD-L1 may protect beta cells against immune-mediated cell death. METHODS: Beta cell lines and human islets were treated with proinflammatory cytokines to model the proinflammatory type 1 diabetes microenvironment. EVs were isolated using ultracentrifugation or size exclusion chromatography and analysed via immunoblot, flow cytometry and ELISA. EV PD-L1 binding to PD-1 was assessed using a competitive binding assay and in vitro functional assays testing the ability of EV PD-L1 to inhibit NOD CD8 RESULTS: PD-L1 protein co-localised with tetraspanin-associated proteins intracellularly and was detected on the surface of beta cell EVs. Treatment with IFN-α or IFN-γ for 24 h induced a twofold increase in EV PD-L1 cargo without a corresponding increase in the number of EVs. IFN exposure predominantly increased PD-L1 expression on the surface of beta cell EVs and beta cell EV PD-L1 showed a dose-dependent capacity to bind PD-1. Functional experiments demonstrated specific effects of beta cell EV PD-L1 to suppress proliferation and cytotoxicity of murine CD8 CONCLUSIONS/INTERPRETATION: IFN exposure increases PD-L1 on the beta cell EV surface. Beta cell EV PD-L1 binds PD1 and inhibits CD8