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

Mads N Olesen; Josefine R Christiansen; Steen Vang Petersen; Poul Henning Jensen; Wojciech Paslawski; Marina Romero-Ramos; Vanesa Sanchez-Guajardo

doi:10.1016/j.heliyon.2018.e00513

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

Heliyon. 2018 Feb 1;4(1):e00513. doi: 10.1016/j.heliyon.2018.e00513. eCollection 2018 Jan.

Authors

Mads N Olesen^{1

2}, Josefine R Christiansen^{1

2

3}, Steen Vang Petersen⁴, Poul Henning Jensen⁵, Wojciech Paslawski⁶, Marina Romero-Ramos^{2

3}, Vanesa Sanchez-Guajardo^{1

2}

Affiliations

¹ Neuroimmunology of Degenerative Diseases Group, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
² AUideas Pilot Center NEURODIN, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
³ CNS Disease Modeling Group, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁴ Laboratory for Redox Regulation, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁵ DANDRITE, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁶ iNANO, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.

Abstract

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-synuclein or its pathology-associated variants, nitrated or fibrillar, to characterize the modulation of the CD4 T cell pool by α-synuclein and brain microglia in the absence of any α-synuclein brain pathology. We observed that α-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 α-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-α-synuclein antibodies. Furthermore, the activation pattern of CD3+CD4+ T cells was modulated in a variant-dependent manner; while nitrated and fibrillar α-synuclein expanded the fraction of activated Treg, all three α-synuclein variants reduced the expression levels of STAT3, CD25 and CD127 on CD3+CD4+ T cells. Additionally, while monomeric α-synuclein increased CD103 expression, the fibrils decreased it, and CCR6 expression was decreased by nitrated and fibrillar α-synuclein, indicating that α-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 α-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 α-synuclein, which results in variant-specific T cell migration into the brain. This may have a specific repercussion for brain microglia.

Keywords: Immunology; Neuroscience.