Neuron-derived exosomes trigger a PD-L1-mediated broad suppression of T cells in Parkinson’s disease

Abstract: Background Adaptive immunity plays an important role in Parkinson’s disease (PD). Multiple lines of evidence indicate a significant decrease in peripheral T cells in PD patients. Although this suppression impacts both overall immune and neuroimmune response in Parkinson’s disease, there is currently no mechanistic explanation for this important phenomenon reported by many clinical studies. Methods The exosomes were isolated from culture media of cell lines overexpressing α-synuclein A53T mutant (A53T-syn), plasma of transgenic mouse expressing A53T-syn, and dopaminergic neuron-specific organoid derived from induced pluripotent stem cells of familial PD patients carrying A53T-syn mutation (termed neuron-derived exosomes or NDEs). Western blot was used to measure the expressions of exosome markers and transmission electron microscopy was used to confirm the morphology of purified exosomes. The CD4 + and CD8 + T cells were purified from mouse spleen using a negative selection method and the effects of NDEs on the cytokines production, activation, and proliferation of purified CD4 + and CD8 + T cells were assessed by flow cytometry. Purified naïve CD4 + T cells were used to examine the effects of NDEs on CD4 + T cell differentiation. Results Exosomes derived from all three sources suppressed IL-4 and INF-γ production by both purified CD4 + and CD8 + T cells and inhibited T cell activation and proliferation. The suppressed phenotype of T cells induced by NDEs was accompanied by a reduction of Th1-promoting transcription factor T-bet and Th2-promoting transcription factor GATA-3 in T cells. Consistently, NDEs isolated from plasma of A53T-syn mice and dopaminergic neuron-specific organoid carrying A53T-syn mutation also suppressed Th1 and Th2 differentiation of naïve CD4 + T cells. Mechanistically, the suppressed phenotype induced by NDEs isolated from PD models 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 induced by A53T-syn exosomes. Conclusions Our study reveals the key role of neuron-derived exosomes in mediating the broad suppression of T cells observed in PD and provides the basis for exploring peripheral T cells in PD pathogenesis and as biomarkers or therapeutic targets for the disease.