α-Synuclein vaccination modulates regulatory T cell activation and microglia in the absence of brain pathology
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α-Synuclein vaccination modulates regulatory T cell activation and microglia in the absence of brain pathology. / Christiansen, Josefine R; Olesen, Mads N; Otzen, Daniel E; Romero-Ramos, Marina; Sanchez-Guajardo, Vanesa.
I: Journal of Neuroinflammation, Bind 13, Nr. 1, 07.04.2016, s. 74.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - α-Synuclein vaccination modulates regulatory T cell activation and microglia in the absence of brain pathology
AU - Christiansen, Josefine R
AU - Olesen, Mads N
AU - Otzen, Daniel E
AU - Romero-Ramos, Marina
AU - Sanchez-Guajardo, Vanesa
PY - 2016/4/7
Y1 - 2016/4/7
N2 - BACKGROUND: Passive and active immunization with α-synuclein has been shown to be neuroprotective in animal models of Parkinson's disease. We have previously shown that vaccination with α-synuclein, long before α-synuclein-induced brain pathology, prevents striatal degeneration by inducing regulatory T cell infiltration in parenchyma and antibody deposition on α-synuclein overexpressing neurons. However, the effect of peripheral α-synuclein on the immune system is unknown, as are the mechanistic changes induced in the CD4 T cell population during successful neuroprotective animal studies. We have studied the changes induced by vaccination with α-synuclein in the CD4 T cell pool and its impact on brain microglia to understand the immune mechanisms behind successful vaccination strategies in Parkinson's disease animal models.METHODS: Mice were immunized with WT or nitrated α-synuclein at a dose equivalent to the one used in our previous successful vaccination strategy and at a higher dose to determine potential dose-dependent effects. Animals were re-vaccinated 4 weeks after and sacrificed 5 days later. These studies were conducted in naive animals in the absence of human α-synuclein expression.RESULTS: The CD4 T cell response was modulated by α-synuclein in a dose-dependent manner, in particular the regulatory T cell population. Low-dose α-synuclein induced expansion of naive (Foxp3 + CCR6-CD127lo/neg) and dopamine receptor type D3+ regulatory T cells, as well as an increase in Stat5 protein levels. On the other hand, high dose promoted activation of regulatory T cells (Foxp3CCR6 + CD127lo/neg), which were dopamine receptor D2+D3-, and induced up-regulation of Stat5 and production of anti-α-synuclein antibodies. These effects were specific to the variant of α-synuclein used as the pathology-associated nitrated form induced distinct effects at both doses. The changes observed in the periphery after vaccination with low-dose α-synuclein correlated with an increase in CD154+, CD103+, and CD54+ microglia and the reduction of CD200R+ microglia. This resulted in the induction of a polarized tolerogenic microglia population that was CD200R-CD54CD103CD172a+ (82 % of total microglia).CONCLUSIONS: We have shown for the first time the mechanisms behind α-synuclein vaccination and, importantly, how we can modulate microglia's phenotype by regulating the CD4 T cell pool, thus shedding invaluable light on the design of neuroimmunoregulatory therapies for Parkinson's disease.
AB - BACKGROUND: Passive and active immunization with α-synuclein has been shown to be neuroprotective in animal models of Parkinson's disease. We have previously shown that vaccination with α-synuclein, long before α-synuclein-induced brain pathology, prevents striatal degeneration by inducing regulatory T cell infiltration in parenchyma and antibody deposition on α-synuclein overexpressing neurons. However, the effect of peripheral α-synuclein on the immune system is unknown, as are the mechanistic changes induced in the CD4 T cell population during successful neuroprotective animal studies. We have studied the changes induced by vaccination with α-synuclein in the CD4 T cell pool and its impact on brain microglia to understand the immune mechanisms behind successful vaccination strategies in Parkinson's disease animal models.METHODS: Mice were immunized with WT or nitrated α-synuclein at a dose equivalent to the one used in our previous successful vaccination strategy and at a higher dose to determine potential dose-dependent effects. Animals were re-vaccinated 4 weeks after and sacrificed 5 days later. These studies were conducted in naive animals in the absence of human α-synuclein expression.RESULTS: The CD4 T cell response was modulated by α-synuclein in a dose-dependent manner, in particular the regulatory T cell population. Low-dose α-synuclein induced expansion of naive (Foxp3 + CCR6-CD127lo/neg) and dopamine receptor type D3+ regulatory T cells, as well as an increase in Stat5 protein levels. On the other hand, high dose promoted activation of regulatory T cells (Foxp3CCR6 + CD127lo/neg), which were dopamine receptor D2+D3-, and induced up-regulation of Stat5 and production of anti-α-synuclein antibodies. These effects were specific to the variant of α-synuclein used as the pathology-associated nitrated form induced distinct effects at both doses. The changes observed in the periphery after vaccination with low-dose α-synuclein correlated with an increase in CD154+, CD103+, and CD54+ microglia and the reduction of CD200R+ microglia. This resulted in the induction of a polarized tolerogenic microglia population that was CD200R-CD54CD103CD172a+ (82 % of total microglia).CONCLUSIONS: We have shown for the first time the mechanisms behind α-synuclein vaccination and, importantly, how we can modulate microglia's phenotype by regulating the CD4 T cell pool, thus shedding invaluable light on the design of neuroimmunoregulatory therapies for Parkinson's disease.
KW - Animals
KW - Blotting, Western
KW - Enzyme-Linked Immunosorbent Assay
KW - Flow Cytometry
KW - Humans
KW - Immunohistochemistry
KW - Lymphocyte Activation/immunology
KW - Mice
KW - Mice, Inbred C57BL
KW - Microglia/immunology
KW - Parkinsonian Disorders/immunology
KW - Recombinant Proteins/immunology
KW - T-Lymphocytes, Regulatory/immunology
KW - Vaccination
KW - alpha-Synuclein/administration & dosage
U2 - 10.1186/s12974-016-0532-8
DO - 10.1186/s12974-016-0532-8
M3 - Journal article
C2 - 27055651
VL - 13
SP - 74
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
SN - 1742-2094
IS - 1
ER -
ID: 390196313