Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease

Abstract

Progressive loss of dopaminergic neurons in the substantia nigra pars compacta and their terminal connections in the striatum are central features in Parkinson's disease (PD). Emerging evidence supports the notion that microglia neuroinflammatory responses speed neurodegenerative events. We demonstrated previously that this can be slowed by adoptive transfer of T cells from Copolymer-1-immunized mice administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) recipients. The cellular basis for this neuroprotective response was the CD4+ T cell population, suggesting involvement of CD4+CD25+ regulatory T cells (Tregs), cells known to suppress immune activation and maintain immune homeostasis and tolerance. We show for the first time that adoptive transfer of CD3-activated Tregs to MPTP-intoxicated mice provides greater than 90% protection of the nigrostriatal system. The response was dose-dependent and paralleled modulation of microglial responses and up-regulation of glial cell-derived neurotrophic factor (CDNF) and TGF-beta. Interestingly, that adoptive transfer of effector T cells showed no significant neuroprotective activities. Tregs were found to mediate neuroprotection through suppression of microglial responses to stimuli, including aggregated, nitrated alpha-synuclein. Moreover, Treg-mediated suppression was also operative following removal of Tregs from culture prior to stimulation. This neuroprotection was achieved through modulation of microglial oxidative stress and inflammation. As Tregs can be modulated in vivo, these data strongly support the use of such immunomodulatory strategies to treat PD.

Dopamine Receptor D3 Expressed on CD4+ T Cells Favors Neurodegeneration of Dopaminergic Neurons during Parkinson’s Disease

“…For this purpose, mice were treated with an acute toxicity regimen of MPTP, and after 7 d, histological analysis of DAergic neuron integrity and neurodegeneration in the SN were performed in midbrain sections by TH immunostaining and FJ-C labeling, respectively. Consistent with previous reports (6,7,10), results show that MPTP treatment of WT mice results in significant loss of DAergic neurons ( 40%) in the SNpc. Strikingly, D3R deficiency completely abolished MPTP-induced loss of DAergic neurons (Fig.…”

“…These studies have shown that nitrated a-synuclein is presented in cervical lymph nodes, which drain Ags from CNS, and elicits an Ag-specific CD4 + T cell response mediated by cells with the inflammatory phenotypes Th1 and Th17, which exacerbate the microglial activation and neuronal damage (5,8). In contrast, it has been demonstrated that CD4 + regulatory T cells (Tregs), which suppress function of inflammatory Th1 and Th17 cells, may also participate during PD, attenuating the destruction of DAergic neurons in the SN (7,10). Thus, this evidence supports the participation of a CD4 + T cell response during PD, which seems to be fundamental for the degeneration of DAergic neurons in the SN.…”

“…Previous studies addressing the role of T cells in PD have shown that DAergic neuronal loss in the SN is associated to proinflammatory phenotypes of CD4 + T cells, such as Th1 and Th17. Conversely, participation of CD4 + T cells with the antiinflammatory phenotype Tregs has been associated to attenuated MPTP-induced loss of TH + neurons in the SN (7,10,38). Accordingly, we next performed experiments to determine the involvement of D3R expressed on CD4 + T cells in the acquisition of proinflammatory and anti-inflammatoty phenotypes described to be relevant for PD.…”

Alpha-Synuclein and the Immune Response in Parkinson’s Disease

“…This neuroprotective effect was later found to be mediated by the CD4 + type of T cells, suggesting the possible involvement of Treg cells (Laurie et al, 2007). Later work by the same group confirmed this hypothesis by showing that passive transfer to MPTP mice of activated Treg cells, but not effector T cells, efficiently suppressed microglial activation and afforded neuroprotection (Reynolds et al, 2007), suggesting that the immunomodulating abilities of Treg cells could potentially be utilized as a therapeutic approach against PD (Stone et al, 2009). …”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…While active immunization stimulates the immune system to produce antibodies against target proteins, passive immunization consists in directly administering antibodies that confer temporary protection against the disease. A third type of immunotherapy involving the activation of regulatory T-cells has also been explored for the potential treatment of AD and PD [59,60]. The advantage of humoral immunotherapy over other approaches is that it allows for the generation of antibodies targeting specific conformations of Aβ, tau, or α-syn (monomers, oligomers, and/or fibrils) (Fig.…”