Exacerbation of neurodegeneration by an α-synuclein specific CD4+ effector T cell line in a mouse model of Parkinson’s disease (HUM1P.326)

Abstract

Abstract We have previously shown in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model that T cell-mediated immunity regulates innate immunity to exacerbate neuroinflammation. Effector T cells that recognize nitrated α-synuclein (N-α-syn) as non-self, increase reactive myeloid microglia and inflammatory mediators with prolonged progression and increased dopaminergic neurodegeneration within the substantia nigra (SN) of MPTP treated mice. This study focuses on the generation of an N-α-syn specific CD4+ T cell line with the ability to increase release of reactive nitrogen species (RNS) from myeloid lineage cells and also intensify the loss of tyrosine hydroxylase (TH) expressing dopaminergic neurons within the SN of MPTP intoxicated mice. Flow cytometric analysis showed the T cell line exhibited very distinct expression of CD3, CD4 and IL-17a, moderate staining for CD146, yet very little expression of CD8 and FoxP3. Co-culture of the T cells with N-α-syn and BV-2 cells increased RNS production of BV-2 cells by 150% compared to controls. Lastly, adoptive transfer of the T cell line to MPTP intoxicated mice exacerbated the loss of TH+ dopaminergic neurons by 63% compared to controls. Together, these results support the notion that effector T cells specific for N-α-syn increase oxidative stress as measured by RNS release from reactive myeloid microglia, increase the loss of TH+ neurons, and thus may play a pivotal role in the tempo and progression of Parkinson’s disease.