T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils
Background: -Synuclein (-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of -synucleinopathies, such as Parkinsons disease (PD) and multiple system atrophy (MSA). Other hallmarks include activation of microglia, elevation of pro-inflammatory cytokines, as well as the activation of T and B cells. These immune changes point towards a dysregulation of both the innate and the adaptive immune system. T cells have been shown to recognize epitopes derived from -syn and altered populations of T cells have been found in PD and MSA patients, providing evidence that these cells can be key to the pathogenesis of the disease. Objective: To study the role of the adaptive immune system with respect to -syn pathology. Methods: We injected human -syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated -syn pathology, proteinase K-resistant -syn pathology and microgliosis in the striatum, substantia nigra and frontal cortex. We also assessed the impact of adoptive transfer of naive T and B cells into PFF-injected immunocompromised mice. Results: Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated -syn pathology in the substantia nigra. Reconstituting the T cell population decreased the accumulation of phosphorylated -syn pathology and resulted in persistent microgliosis in the striatum when compared to non-transplanted mice. Conclusion: Our work provides evidence that T cells play a role in the pathogenesis of experimental -synucleinopathy.