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

Zhichun Chen; Wenming Li; Bo Meng; Chongchong Xu; Yiqi Huang; Guanglu Li; Zhexing Wen; Jun Liu; Zixu Mao

doi:10.1016/j.isci.2024.110243

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

iScience. 2024 Jun 11;27(7):110243. doi: 10.1016/j.isci.2024.110243. eCollection 2024 Jul 19.

Authors

Zhichun Chen^{1

2

3}, Wenming Li¹, Bo Meng¹, Chongchong Xu⁴, Yiqi Huang⁵, Guanglu Li², Zhexing Wen^{4

6}, Jun Liu², Zixu Mao^{1

6

7}

Affiliations

¹ Departments of Pharmacology & Chemical Biology and Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
² Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
³ Department of Neurology, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, China.
⁴ Departments of Psychiatry and Behavioral Sciences and Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁵ The Graduate Program in Neuroscience, Laney Graduate School, Emory University, Atlanta, GA 30322, USA.
⁶ Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
⁷ Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA 30322, USA.

Abstract

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.

Keywords: Biological sciences; Cellular neuroscience; Natural sciences; Neuroscience; Systems neuroscience.