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Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease.

ABSTRACT: Nitrated alpha-synuclein (N-alpha-syn) immunization elicits adaptive immune responses to novel antigenic epitopes that exacerbate neuroinflammation and nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. We show that such neuroimmune degenerative activities, in significant measure, are Th17 cell-mediated, with CD4(+)CD25(+) regulatory T cell (Treg) dysfunction seen among populations of N-alpha-syn-induced T cells. In contrast, purified vasoactive intestinal peptide induced and natural Tregs reversed N-alpha-syn T cell nigrostriatal degeneration. Combinations of adoptively transferred N-alpha-syn and vasoactive intestinal peptide immunocytes or natural Tregs administered to MPTP mice attenuated microglial inflammatory responses and led to robust nigrostriatal protection. Taken together, these results demonstrate Treg control of N-alpha-syn-induced neurodestructive immunity and, as such, provide a sound rationale for future Parkinson's disease immunization strategies.

SUBMITTER: Reynolds AD

PROVIDER: S-EPMC2824790 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease.

Reynolds Ashley D AD Stone David K DK Hutter Jessica A L JA Benner Eric J EJ Mosley R Lee RL Gendelman Howard E HE

Journal of immunology (Baltimore, Md. : 1950) 20100129 5

Nitrated alpha-synuclein (N-alpha-syn) immunization elicits adaptive immune responses to novel antigenic epitopes that exacerbate neuroinflammation and nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. We show that such neuroimmune degenerative activities, in significant measure, are Th17 cell-mediated, with CD4(+)CD25(+) regulatory T cell (Treg) dysfunction seen among populations of N-alpha-syn-induced T cells. In contrast, purif ...[more]

PMID: 20118279

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Project description:ObjectiveThe dopaminergic nigrostriatal neurons (DA cells) in healthy people present a slow degeneration with aging, which produces cellular debris throughout life. About 2%-5% of people present rapid cell degeneration of more than 50% of DA cells, which produces Parkinson's disease (PD). Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells, particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons. As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation, this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells, paying particular attention to the relative roles of astrocytes and microglia.MethodsRats and mice were injected in the lateral ventricles with 6-hydroxydopamine, inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage, microgliosis or neuroinflammation. The possible retrograde degeneration of dopaminergic axons, and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images.ResultsThe selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle. These spheroids retained mitochondria and most (e.g., tyrosine hydroxylase, the dopamine transporter protein, and amyloid precursor protein) but not all (e.g., α-synuclein) proteins of the degenerating dopaminergic axons. Spheroids showed initial (autophagosomes) but not late (lysosomes) components of autophagy (incomplete autophagy). These spheroids were penetrated by astrocytic processes of the medial forebrain bundle, which provided the lysosomes needed to continue the degradation of dopaminergic debris. Finally, dopaminergic proteins were observed in the cell somata of astrocytes. No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons.ConclusionsThe present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes, which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.

Dataset Information

Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease.

Publications

Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease.

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