Neuronal-enriched small extracellular vesicles trigger a PD-L1-mediated broad suppression of T cells in Parkinson’s disease

• Published in: iScience Vol. 27; no. 7; p. 110243
• Main Authors: Chen, Zhichun, Li, Wenming, Meng, Bo, Xu, Chongchong, Huang, Yiqi, Li, Guanglu, Wen, Zhexing, Liu, Jun, Mao, Zixu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.07.2024; Elsevier
• Subjects: Biological sciences; Cellular neuroscience; Natural sciences; Neuroscience; Systems neuroscience; Systems neuroscience; Neuroscience; Biological sciences; Natural sciences; Cellular neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.110243

Many clinical studies indicate a significant decrease of peripheral T cells in Parkinson’s disease (PD). There is currently no mechanistic explanation for this important observation. Here, we found that small extracellular vesicles (sEVs) derived from in vitro and in vivo PD models suppressed IL-4 and INF-γ production from both purified CD4+ and CD8+ T cells and inhibited their activation and proliferation. Furthermore, neuronal-enriched sEVs (NEEVs) isolated from plasma of A53T-syn mice and culture media of human dopaminergic neurons carrying A53T-syn mutation also suppressed Th1 and Th2 differentiation of naive CD4+ T cells. Mechanistically, the suppressed phenotype induced by NEEVs was associated with altered programmed death ligand 1 (PD-L1) level in T cells. Blocking PD-L1 with an anti-PD-L1 antibody or a small molecule inhibitor BMS-1166 reversed T cell suppression. Our study provides the basis for exploring peripheral T cells in PD pathogenesis and as biomarkers or therapeutic targets for the disease. [Display omitted] •NEEVs derived from in vitro and in vivo PD models suppress CD4+ and CD8+ T cells•NEEVs isolated from PD models suppress Th1 and Th2 differentiation•The suppressed phenotype is associated with increased PD-L1 level in T cells•Blocking PD-L1 with an anti-PD-L1 antibody or BMS-1166 reverses T cell suppression Natural sciences; Biological sciences; Neuroscience; Systems neuroscience; Cellular neuroscience