Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Olesen, Mads N., Christiansen, Josefine R., Petersen, Steen Vang, Jensen, Poul Henning, Paslawski, Wojciech, Romero-Ramos, Marina, Sanchez-Guajardo, Vanesa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857520/
https://www.ncbi.nlm.nih.gov/pubmed/29560431
http://dx.doi.org/10.1016/j.heliyon.2018.e00513
_version_ 1783307476918075392
author Olesen, Mads N.
Christiansen, Josefine R.
Petersen, Steen Vang
Jensen, Poul Henning
Paslawski, Wojciech
Romero-Ramos, Marina
Sanchez-Guajardo, Vanesa
author_facet Olesen, Mads N.
Christiansen, Josefine R.
Petersen, Steen Vang
Jensen, Poul Henning
Paslawski, Wojciech
Romero-Ramos, Marina
Sanchez-Guajardo, Vanesa
author_sort Olesen, Mads N.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5857520
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-58575202018-03-20 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 Olesen, Mads N. Christiansen, Josefine R. Petersen, Steen Vang Jensen, Poul Henning Paslawski, Wojciech Romero-Ramos, Marina Sanchez-Guajardo, Vanesa Heliyon Article 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. Elsevier 2018-02-01 /pmc/articles/PMC5857520/ /pubmed/29560431 http://dx.doi.org/10.1016/j.heliyon.2018.e00513 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Olesen, Mads N.
Christiansen, Josefine R.
Petersen, Steen Vang
Jensen, Poul Henning
Paslawski, Wojciech
Romero-Ramos, Marina
Sanchez-Guajardo, Vanesa
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857520/
https://www.ncbi.nlm.nih.gov/pubmed/29560431
http://dx.doi.org/10.1016/j.heliyon.2018.e00513
work_keys_str_mv AT olesenmadsn cd4tcellsreacttolocalincreaseofasynucleininapathologyassociatedvariantdependentmannerandmodifybrainmicrogliainabsenceofbrainpathology
AT christiansenjosefiner cd4tcellsreacttolocalincreaseofasynucleininapathologyassociatedvariantdependentmannerandmodifybrainmicrogliainabsenceofbrainpathology
AT petersensteenvang cd4tcellsreacttolocalincreaseofasynucleininapathologyassociatedvariantdependentmannerandmodifybrainmicrogliainabsenceofbrainpathology
AT jensenpoulhenning cd4tcellsreacttolocalincreaseofasynucleininapathologyassociatedvariantdependentmannerandmodifybrainmicrogliainabsenceofbrainpathology
AT paslawskiwojciech cd4tcellsreacttolocalincreaseofasynucleininapathologyassociatedvariantdependentmannerandmodifybrainmicrogliainabsenceofbrainpathology
AT romeroramosmarina cd4tcellsreacttolocalincreaseofasynucleininapathologyassociatedvariantdependentmannerandmodifybrainmicrogliainabsenceofbrainpathology
AT sanchezguajardovanesa cd4tcellsreacttolocalincreaseofasynucleininapathologyassociatedvariantdependentmannerandmodifybrainmicrogliainabsenceofbrainpathology