CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson's disease

There is no consensus on the exact role of the adaptive immune system in Parkinson's disease pathogenesis, although there is increasing evidence that it is somehow involved. Moreover, T cell infiltration in the brain has not been thoroughly studied in Parkinson's disease and no study has assessed the infiltration in incidental Lewy body diseases cases that are considered to be early presymptomatic stages of the disease. In this study, we performed an immunohistochemistry/immunofluorescence quantitative and phenotypic assessment of T cell infiltration in human substantia nigra pars compacta and analysed the correlations with neuronal death and synucleinopathy throughout different stages of the disease. We included two groups of incidental Lewy disease in the study. One of the groups, which is believed to be the earliest stage of the disease, showed alpha-synuclein aggregates only in the olfactory bulb. The second group also presented alpha-synuclein aggregates in the substantia nigra. We also assessed the formation of different alpha-synuclein aggregates throughout the different stages of the unified staging system for Lewy body disorders (I to IV). We found that CD8 T cells were increased in diagnosed Parkinson's disease cases compared to the control group and their density positively correlated with neuronal death. Some of the infiltrating CD8 T cells were indeed contacting dopaminergic neurons. No differences were found regarding CD4 T cells. In the earliest stage of the disease, when substantia nigra alpha-synuclein aggregation is absent, we found a robust CD8 T cell infiltration and no dopaminergic neuronal death yet. Conversely, in the next stage we found neuronal loss and a milder CD8 T cell infiltration. CD8 T cell infiltration paralleled that of alpha-synuclein accumulation and neuronal death throughout stages II to IV. We also confirmed that CD8 T cells in charge of immune surveillance and involved in the aetiopathogenesis of the disease are equipped with cytolytic enzymes (granzyme A, B and K) and/or proinflammatory cytokines (interferon gamma), and that phenotypic differences were observed between early and late stages of the disease. We also demonstrate that a high proportion of nigral CD8 T cells are tissue resident memory T cells. Our results show that nigral cytotoxic CD8 T cell infiltration is an earlier pathogenic event than alpha-synuclein aggregation and neuronal death and that it parallels the progression of neuronal death and synucleinopathy in Parkinson's disease. Overall, our study suggests that CD8 T cell cytotoxic attack may initiate and propagate neuronal death and synucleinopathy in Parkinson's disease.