α-Synuclein orchestrates Th17 responses as antigen and adjuvant in Parkinson's disease

Recently, the role of T cells in the pathology of alpha-synuclein (alpha S)-mediated neurodegenerative disorders called synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy, has attracted increasing attention. Although the existence of alpha S-specific T cells and the immunogenicity of the post-translationally modified alpha S fragment have been reported in PD and DLB, the key cellular subset associated with disease progression and its induction mechanism remain largely unknown. Peripheral blood mononuclear cells (PBMCs) from synucleinopathy patients and healthy controls were cultured in the presence of the alpha S peptide pools. Cytokine analysis using culture supernatants revealed that C-terminal alpha S peptides with a phosphorylated serine 129 residue (pS129), a feature of pathological alpha S aggregates, promoted the production of IL-17A, IL-17F, IL-22, IFN-gamma and IL-13 in PD patients compared with that in controls. In pS129 peptide-reactive PD cases, Ki67 expression was increased in CD4 T cells but not in CD8 T cells, and intracellular cytokine staining assay revealed the existence of pS129 peptide-specific Th1 and Th17 cells. The pS129 peptide-specific Th17 responses, but not Th1 responses, demonstrated a positive correlation with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III scores. A similar correlation was observed for IL-17A levels in the culture supernatant of PBMCs from PD patients with disease duration < 10 years. Interestingly, enhanced Th17 responses to pS129 peptides were uniquely found in PD patients among the synucleinopathies, suggesting that Th17 responses are amplified by certain mechanisms in PD patients. To investigate such mechanisms, we analyzed Th17-inducible capacity of alpha S-exposed dendritic cells (DCs). In vitro stimulation with alpha S aggregates generated Th17-inducible DCs with IL-6 and IL-23 production through the signaling of TLR4 and spliced X-box binding protein-1 (XBP1s). In fact, the levels of IL-6 and IL-23 in plasma, and the XBP1s ratio in type 2 conventional DCs were increased in PD patients compared with those in controls. Here, we propose the importance of alpha S-specific Th17 responses in the progression of PD and the underlying mechanisms inducing Th17 responses. These findings may provide novel therapeutic strategies to prevent disease development through the suppression of TLR4-XBP1s-IL-23 signaling in DCs.