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CD4 T cells react to local increase of ?-synuclein in a pathology-associated variant-dependent manner and modify brain microglia in absence of brain pathology.

ABSTRACT: We have previously shown that immunological processes in the brain during ?-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 ?-synuclein pathology. However, it was unclear whether these immune changes were governed by brain processes or by a direct immune response to ?-synuclein modifications. We have herein locally increased the peripheral concentration of ?-synuclein or its pathology-associated variants, nitrated or fibrillar, to characterize the modulation of the CD4 T cell pool by ?-synuclein and brain microglia in the absence of any ?-synuclein brain pathology. We observed that ?-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 ?-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-?-synuclein antibodies. Furthermore, the activation pattern of CD3+CD4+ T cells was modulated in a variant-dependent manner; while nitrated and fibrillar ?-synuclein expanded the fraction of activated Treg, all three ?-synuclein variants reduced the expression levels of STAT3, CD25 and CD127 on CD3+CD4+ T cells. Additionally, while monomeric ?-synuclein increased CD103 expression, the fibrils decreased it, and CCR6 expression was decreased by nitrated and fibrillar ?-synuclein, indicating that ?-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 ?-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 ?-synuclein, which results in variant-specific T cell migration into the brain. This may have a specific repercussion for brain microglia.

SUBMITTER: Olesen MN

PROVIDER: S-EPMC5857520 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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CD4 T cells react to local increase of α-synuclein in a pathology-associated variant-dependent manner and modify brain microglia in absence of brain pathology.

Olesen Mads N MN Christiansen Josefine R JR Petersen Steen Vang SV Jensen Poul Henning PH Paslawski Wojciech W Romero-Ramos Marina M Sanchez-Guajardo Vanesa V

Heliyon 20180101 1

We have previously shown that immunological processes in the brain during α-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 α-synuclein pathology. However, it was unclear whether these immune changes were governed by brain processes or by a direct immune response to α-synuclein modifications. We have herein locally increased the peripheral concentration of α-s ...[more]

PMID: 29560431

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Dataset Information

CD4 T cells react to local increase of ?-synuclein in a pathology-associated variant-dependent manner and modify brain microglia in absence of brain pathology.

Publications

CD4 T cells react to local increase of α-synuclein in a pathology-associated variant-dependent manner and modify brain microglia in absence of brain pathology.

Similar Datasets

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