CD8+ T cells in synucleinopathies: differential immune mechanisms in Parkinson's disease and multiple system atrophy

Synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy (MSA), are characterized by α-synuclein aggregation and progressive neurodegeneration. Increasing evidence implicates adaptive immune mechanisms, particularly CD8+ T cells, in their pathogenesis.

To summarize and compare the role of CD8+ T lymphocytes in PD and MSA, with an emphasis on disease-specific immune mechanisms.

A structured narrative review of PubMed, Embase, and Scopus databases was performed, and 15 relevant studies were included.

In PD, CD8+ T cells infiltrate the substantia nigra at early disease stages, often preceding overt neurodegeneration and α-synuclein deposition, and exhibit a cytotoxic phenotype characterized by granzyme and interferon-γ expression, with potential direct interactions with MHC class I-expressing neurons. Peripheral findings further support a CD8-dominant immune response with expansion of cytotoxic subsets. In contrast, MSA is associated with a relatively CD4-dominant immune profile, with increased CD4/CD8 ratios and a broader inflammatory environment, in which CD8+ T cells appear to play a more modulatory role. Across synucleinopathies, CD8+ T cells demonstrate regional CNS infiltration, phenotypic heterogeneity, and association with microglial activation.

CD8+ T cells represent a heterogeneous and context-dependent component of adaptive immunity in synucleinopathies, with a predominantly cytotoxic and potentially pathogenic role in PD and a more modulatory function in MSA. These disease-specific d ifferences pr ovide in sight in to un derlying ne uroimmune me chanisms an d su pport th e po tential of CD8+ T-cell-related pathways as biomarkers and targets for tailored immunomodulatory strategies.