Table 3.
Evidence for the role of T lymphocytes in Parkinson's disease.
| Specimens | Study groups | Main findings | References |
|---|---|---|---|
| Human PBMCs and plasma | PD patient and HS | • Decreased levels of Tregs observed in PD patients compared to controls • No significant difference in Th1, Th2, and Th17 levels between patients and control, however serum levels of IL-17A were decreased in PD patients • Serum levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and GM-CSF not significantly different between groups |
(135) |
| Human whole blood | PD patient and HS | • Overall lymphocyte numbers were reduced • CD4+ T cell levels were reduced, CD8+ T cells increased • Treg cells were significantly reduced • IL-4 producing cells were significantly reduced, IFN-γ/IL-4 ratio was significantly increased |
(136) |
| Human whole blood Rodent in vivo | PD patient and HS MPTP+, MPTP− 6-OHDA+, 6−OHDA- | • Decreased lymphocyte numbers, both B and T cells were reduced • CD4+ T cells decreased, CD8+ T cells were consistent • Significant increase in activated CD4+ T cells and reduction in naïve and memory CD4+ T cells • MPTP, but not 6-OHDA treatment, induced activation of CD4+ T cells |
(137) |
| Human post-mortem tissue Rodent in vivo | PD patient and HS MPTP+, MPTP− Tcrb−/−, Rag1−/−, CD4−/−, CD8−/− | • Post-mortem tissue of PD patients and MPTP-mouse model demonstrates infiltration of CD8+ and CD4+ T cells in PD • MHCI expression was observed on dopamine neurons of the SN in PD post-mortem samples • MPTP-induced neurodegeneration decreased in the absence of T cells and cell death was attenuated by a lack of CD4+ T cells not CD8+ T cell |
(138) |
| Human post-mortem tissue and hESC | PD patient and HS | • Microglia conditioned media from α-syn and neuromelanin activated microglia cause expression of MHCI in Vm-neurons • Vm-neurons are capable of inducing proliferation of cytotoxic T lymphocytes which in turn cause neuronal cell death |
(139) |
| Rodent in vivo, in vitro primary microglia and CD4+ T cells | AAV2-Syn or AAV2-GFP and WT or MHCII−/− | • Overexpression of α-syn causes increased expression of MHCII on microglia • Knockout of MHCII attenuates α-syn-induced microglial activation in the SN pars compacta and dopaminergic cell loss |
(140) |
| Human whole blood and isolated PBMCs | PD patient and HS | • PD patients demonstrate lower absolute counts but not frequency of Th17 cells and Tregs • PHA stimulation caused greater increase in IFN-γ and TNF-α in PD patients than HS, however no difference in IL-17A was observed and IL-10 was increased in HS but not in PD patients relative to non-stimulated cells • Co-culture of Teff and Treg cells caused ~80% reduction of IFN-γ and TNF-α in HS but only ~20% in PD patients |
(141) |
| Human PBMCs | PD patient, AD patient and HS | • Increased α-syn specific T-cell reactivity prior to PD diagnosis declining post-diagnosis • Increased T cell reactivity in response to α-syn in PD patients compared to AD patients and HS |
(142) |
| Rodent, in vivo, in vitro neurons and T cells | MPTP+ and MPTP− | • MPTP+ mice demonstrate BBB disruption and infiltration of Th17 cells in SN • IL-17, IL-1β, TNF-α, iNOS, IL-22, and IFN-γ increase in the SN of MPTP+ mice, BDNF and GDNF decrease • Co-culture of Th17 cells with Vm-neurons causes increased TNF-α and IL-1β, and induces neuronal cell death via LFA-1/ICAM-1 |
(143) |
| Rodent, in vivo, in vitro microglia, neurons and Th17 cells | MPTP+ and MPTP− | • MPTP caused BBB disfunction and increased IL-17A in SN only • Teff cells increase the frequency of CD4+ T cells, reduce TH+ cell numbers in the SN, decrease dopamine levels in the striatum and increase IL-1β and TNF-α levels in MPTP mice • Knockout of IL-17A alleviates these effects • IL-17A-induced neuronal cell death does not occur in the absence of microglia • Silencing IL-17A receptor on microglia prevents IL-17-induced cell death |
(144) |
| Rodent, in vivo, in vitro Treg, Teff and microglia | MPTP+ and MPTP− | • Adoptive transfer of Treg attenuates MPTP-induced microglial activation and neuronal cell loss • Adoptive transfer of Treg increase neurotrophic factors; BDNF and GDNF |
(145) |
| Rodent, in vivo, in vitro CD4+ T cells | MPTP+ and MPTP− | • α-syn induced Th1/Th17 cell phenotypes from naïve T cells • Adoptive transfer of α-syn stimulated Th1 and Th17 cells caused neuronal death in the SN, and increases cell death observed in MPTP model |
(146) |
| Rodent, in vivo | WTS+/Rag2+, WTS+ /Rag2−, WTS+/Rag− and WTS−/Rag2+ | • Increased levels of insoluble α-syn in Rag+ mice compared to Rag− mice • CD4+ and CD8+ T cells observed in the brain of WTS+/Rag+ mice but not in WTS+/Rag− or WTS− |
|
| • M1 phenotype prominent in WTS+/Rag− mice compared with an M2 phenotype in WTS+/Rag− mice which demonstrate increased phagocytosis of α-syn | (147) | ||
| Human iPSC and T cells | PD patient and HS | • Increased frequencies of IL-17 producing CD4+ T cells in PD patients, no significant difference in IFN-γ or IL-4 producing cells • Co-culture of iPSC-midbrain neurons with Th17 cells/IL-17 increased neuronal cell death and levels of IL-17, IL-1β, TNF-α, and IL-6 in PD cells • Neuronal cell death in PD co-cultures occurred via IL-17/IL-17 receptor signalling, and potential activation of the NF-κB signalling pathway and preventing IL-17/IL-17 receptor interaction attenuated this |
(148) |
| Human whole blood | PD patient and HS | • Reduced levels of B and T lymphocytes in PD patients | (149) |
| Human isolated PBMCs | PD patient and HS | • α-syn peptides presented by both MHCI and MHCII induce T cell proliferation in PD patients • T cells mainly either IFN-γ or IL-5 producing |
(150) |
| Rodent, in vivo | AAV2-Syn or AAV2-GFP | • α-syn overexpression caused increased expression of CD68, IgG deposition and increased ICAM-1, IL-6, IL-1α, and TNF-α levels • COX-2 remained unchanged and iNOS expression decreased at a later time point • Increased levels of CD3+ and CD45R+ cells following α-syn overexpression |
(151) |
6-OHDA, 6-hydroxydopamine; Teff, T effector cells; Vm, ventral midbrain; HS, healthy subjects; PHA, phytohemagglutinin; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Rag, recombination activation gene; Tcrb, T cell receptor beta; PBMC, peripheral blood mononuclear cell; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase 2; AAV2, adeno-associated viral vector, serotype 2; WTS, human wild type α-syn overexpressing.