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

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.

Oligodendroglial α‐synucleinopathy‐driven neuroinflammation in multiple system atrophy

“…An increased number of myeloid cells may be related to either an enhanced proliferation of resident microglia or infiltration of peripheral monocytes and macrophages. Infiltration of peripheral cells in the brain parenchyma was identified in human post‐mortem brain tissue of PD patients as well as its corresponding mouse models . Recent studies have identified distinct macrophage subsets located in the choroid plexus, the meninges as well as the perivascular space expressing similar surface markers and contributing to defense mechanisms in neurodegenerative diseases .…”

“…The classical markers commonly used to identify resting and activated myeloid cells, such as IBA1, CD11b and CD68, do not allow exact distinction between resident microglia and infiltrated myeloid cells . In contrast, recruitment of peripheral myeloid cells as well as lymphocytes is described in human post‐mortem brain tissue of PD patients as well as in respective in vitro and in vivo models . Besides myeloid cells, astrocytes are also activated by oligodendroglial α‐syn leading to morphological changes and cytokine production .…”

Zooming in on Cryopreservation of hiPSCs and Neural Derivatives: A Dual-Center Study Using Adherent Vitrification

“…Respective fibroblasts were previously reprogrammed from controls and patients suffering from PD (Fig. B) . HiPSCs and smNPCs were cryopreserved via slow‐rate freezing in suspension and adherent vitrification in the TWIST substrate and analyzed after thawing (Fig.…”

“…The smNPCs were generated using an adapted version of a published protocol for a dual‐SMAD‐based generation of midbrain neurons from hiPSCs (Fig. A) . The cryopreservation experiments were designed using the same groups and freezing conditions as for the hiPSCs (Fig.…”

Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia

“…A recent study conducted in mice demonstrates a clonal T cell expansion within the brain of old mice with high levels of IFN-γ, suggesting a role for T cellderived IFN-γ in the age-dependent decline of brain function 65 . Given the presence of T lymphocytes in PD brains and the increasing evidence pointing towards a role for T cell responses in disease pathogenesis 66,67,68 , T-cells could be the main source of IFN-γ, which, in turn, induces LRRK2 expression in neurons and microglia, leading to neuronal damage and inflammatory reactions. Thus, further studies are warranted to investigate the role of IFN signaling in specific brain regions and the role of IFN-γ producing T-cells in ageing and PD.…”