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Cell Stem Cell. 2018 Jul 5;23(1):123-131.e6. doi: 10.1016/j.stem.2018.06.015.

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease.

Author information

1
Department of Stem Cell Biology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany; IZKF Junior Research Group 3 and BMBF Research Group Neuroscience, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
2
Department of Molecular Neurology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
3
Department of Stem Cell Biology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
4
IZKF Junior Research Group 3 and BMBF Research Group Neuroscience, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
5
Department of Stem Cell Biology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany; Department of Anesthesiology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
6
Department of Neuropathology, Regensburg University Hospital, 93053 Regensburg, Germany.
7
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
8
Institute of Biochemistry (Emil-Fischer-Center), Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany.
9
Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
10
Department of Stem Cell Biology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany; IZKF Junior Research Group 3 and BMBF Research Group Neuroscience, Interdisciplinary Center for Clinical Research, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: iryna.prots@uk-erlangen.de.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of midbrain neurons (MBNs). Recent evidence suggests contribution of the adaptive immune system in PD. Here, we show a role for human T lymphocytes as cell death inducers of induced pluripotent stem cell (iPSC)-derived MBNs in sporadic PD. Higher Th17 frequencies were found in the blood of PD patients and increased numbers of T lymphocytes were detected in postmortem PD brain tissues. We modeled this finding using autologous co-cultures of activated T lymphocytes and iPSC-derived MBNs of sporadic PD patients and controls. After co-culture with T lymphocytes or the addition of IL-17, PD iPSC-derived MBNs underwent increased neuronal death driven by upregulation of IL-17 receptor (IL-17R) and NFκB activation. Blockage of IL-17 or IL-17R, or the addition of the FDA-approved anti-IL-17 antibody, secukinumab, rescued the neuronal death. Our findings indicate a critical role for IL-17-producing T lymphocytes in sporadic PD.

KEYWORDS:

Sporadic Parkinson’s disease; T lymphocytes; Th17 cells; human autologous co-culture; neuroinflammation

PMID:
29979986
DOI:
10.1016/j.stem.2018.06.015
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