Early-to-mid stage idiopathic Parkinson’s disease shows enhanced cytotoxicity and differentiation in CD8 T-cells in females

Neuroinflammation in the brain contributes to the pathogenesis of Parkinson’s disease (PD), but the potential dysregulation of peripheral immunity has not been systematically investigated for idiopathic PD (iPD). Here we showed an elevated peripheral cytotoxic immune milieu, with more terminally-differentiated effector memory (TEMRA) CD8 T, CD8+ NKT cells and circulating cytotoxic molecules in fresh blood of early-to-mid iPD, especially in females, after analyzing >700 innate and adaptive features. This profile, also reflected by fewer CD8+FOXP3+ regulatory T cells, was confirmed in another subcohort. Co-expression between cytotoxic molecules was selectively enhanced in CD8 TEMRA and effector memory (TEM) cells. Single-cell RNA-sequencing analysis demonstrated the accelerated CD8 differentiation within CD8 compartments, enhanced cytotoxic pathways in CD8 TEMRA and TEM cells, while CD8 central-memory (TCM) and naïve cells were already more-active and transcriptionally-reprogrammed. Our work provides a comprehensive map of dysregulated peripheral immunity in iPD, proposing previously-unrecognized candidates for early diagnosis and treatments. We compared samples between patients with early-to-mid idiopathic Parkinson’s diseases (iPD) and age-matched healthy controls (HC). Four HC were 59-65 years old (mean=62.33) while five iPD were 56-68 years old (mean=63.14) when they were sampled. Considering our female-biased data in clinical diagnostic values, we only selected female iPD vs age-matched HC for scRNA-seq. All the iPD and HC are CMV seropositive (for other inclusion and exclusion criteria, please refer to the manuscript). All the iPD have a Hoehn and Yahr (H&Y) staging scale of 2. All the PBMC were cryopreserved at the Luxembourg biobank (IBBL) and thawed (for detailed procedures, please refer to the manuscript text). After thawing, PBMC from each participant were stained with marker Abs and sorted into four CD8 subsets: CD8 Naïve (CD45RO-CCR7+), CD8 TCM (CD45RO+CCR7+), CD8 TEM (CD45RO+CCR7-) and CD8 TEMRA (CD45RO-CCR7-). For each subset, we pooled the sorted samples from the same group (HC or iPD) prior to scRNA-seq. The processed files provided in this dataset are the starting point of our scRNA-seq analysis. For detailed analysis steps, please refer to the Methods section of our manuscript including all the code depository information.