CD4 Tcellsreacttolocal increase of α-synuclein in a pathology-associated variant-dependent manner and modify brain microglia in absence of brain pathology

We have previously shown that immunological processes in the brain during alpha-synuclein-induced neurodegeneration vary depending on the presence or absence of cell death. This suggests that the immune system is able to react differently to the different stages of alpha-synuclein pathology. However, it was unclear whether these immune changes were governed by brain processes or by a direct immune response to alpha-synuclein modifications. We have herein locally increased the peripheral concentration of alpha-synuclein or its pathology-associated variants, nitrated or fibrillar, to characterize the modulation of the CD4 T cell pool by alpha-synuclein and brain microglia in the absence of any alpha-synuclein brain pathology. We observed that alpha-synuclein changed the CD4:CD8 ratio by contracting the CD3 +CD4+ T cell pool and reducing the pool of memory Regulatory T cells (Treg). Nitrated alpha-synuclein induced the expansion of both the CD3+CD4+ and CD3 +CD4- T cells, while fibrils increased the percentage of Foxp3+ Treg cells and induced anti-alpha-synuclein antibodies. Furthermore, the activation pattern of CD3 +CD4+ T cells was modulated in a variant-dependent manner; while nitrated and fibrillar alpha-synuclein expanded the fraction of activated Treg, all three alpha-synuclein variants reduced the expression levels of STAT3, CD25 and CD127 on CD3+CD4 + T cells. Additionally, while monomeric alpha-synuclein increased CD103 expression, the fibrils decreased it, and CCR6 expression was decreased by nitrated and fibrillar alpha-synuclein, indicating that alpha-synuclein variants affect the homing and tolerance capacities of CD3+CD4+ T cells. Indeed, this correlated with changes in brain microglia phenotype, as determined by FACS analysis, in an alpha-synuclein variant-specific manner and coincided in time with CD4+ T cell infiltration into brain parenchyma. We have shown that the peripheral immune system is able to sense and react specifically to changes in the local concentration and structure of alpha-synuclein, which results in variant-specific T cell migration into the brain. This may have a specific repercussion for brain microglia.