Regulatory T Cells Attenuate Th17 Cell-Mediated Nigrostriatal Dopaminergic Neurodegeneration in a Model of Parkinson's Disease

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 neuroimmu...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2010-03, Vol.184 (5), p.2261-2271
Main Authors: Reynolds, Ashley D, Stone, David K, Hutter, Jessica A. L, Benner, Eric J, Mosley, R. Lee, Gendelman, Howard E
Format: Article
Language:English
Subjects:
Adoptive Transfer
alpha-Synuclein - pharmacology
Animals
CD4-Positive T-Lymphocytes - drug effects
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - metabolism
Corpus Striatum - drug effects
Corpus Striatum - metabolism
Corpus Striatum - pathology
Dopamine - metabolism
Flow Cytometry
Humans
Immunohistochemistry
Interferon-gamma - metabolism
Interleukin-17 - metabolism
Interleukin-2 Receptor alpha Subunit - metabolism
Male
Mice
Mice, Inbred C57BL
MPTP Poisoning - immunology
MPTP Poisoning - metabolism
MPTP Poisoning - therapy
Neurons - drug effects
Neurons - immunology
Neurons - metabolism
Substantia Nigra - drug effects
Substantia Nigra - metabolism
Substantia Nigra - pathology
T-Lymphocytes, Helper-Inducer - immunology
T-Lymphocytes, Helper-Inducer - metabolism
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
T-Lymphocytes, Regulatory - transplantation
Tumor Necrosis Factor-alpha - metabolism
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.0901852