Nitrated α-Synuclein-Induced Alterations in Microglial Immunity Are Regulated by CD4+ T Cell Subsets

Abstract

Linkages between DA neurodegeneration and microglial neuroinflammatory activities are well-known and demonstrated by large numbers of immune-competent microglia within the substantia nigra of postmortem PD brains (7) appearing as phagocytic cells engulfing damaged DA neurons (7,8). In transgenic mutant ␣-syn mice and in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone (8 -10), similar microglial responses are operative. Importantly, such microglial activation is associated with ␣-syn deposition (11-13) and internalization (14). This occurs throughout disease, suggesting linkages to oxidative damage, ␣-syn nitration and aggregation, and PD-associated neurodegeneration (15, 16) Indeed, microglial activation is strongly associated with neurotoxic responses and collateral neuronal damage (17)(18)(19)(20). Thus, for PD, nitrated-␣-syn (N-␣-syn)-mediated microglial activation and accelerated neuronal death are closely related (21-25).Abundant evidence indicates a significant role for adaptive immunity in neuroregulatory activities (26 -29). Such effects are seen in experimental neurodegenerative models, including PD (29 -31). Principally, these data found that neuronal degeneration or protection is linked to the microglial phenotype and that N-␣-syn-specific effector T cells exacerbate microglial activation and DA neurodegeneration, whereas CD4 ϩ CD25ϩ regulatory T cells (Treg) attenuate those processes; however, how microglia activation is regulated by regulatory and effector T cell subsets is not known. To address this, we used aggregated N-␣-syn as an inducer of microglial activation (23, 24), then studied the microglial immune response as it is affected by activated Treg and CD4 ϩ CD25Ϫ effector T cells (Teff). The observations demonstrate, for the first time, that Treg modulate a broad range of microglial activities, including redox biology, migration, phagocytosis, energy metabolism, and cytokine secretions. Differential outcomes of microglial processes are dependent on the temporal engagement of Treg with N-␣-syn and microglia. The findings provide insights into disease pathobiology and how the adaptive immune system may be harnessed for therapeutic benefit.

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

“…In this regard, nitrated a-synuclein, a major component of the Lewy bodies observed on PD, has been suggested as one of the neoantigens recognized by the adaptive immune system during PD (5,7,8). Importantly, nitrated a-synuclein is not only present in mice undergoing PD but also in brains of PD patients (5,9).…”

“…Importantly, nitrated a-synuclein is not only present in mice undergoing PD but also in brains of PD patients (5,9). 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).…”

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

“…Based on results obtained with an MPTP murine model of the disease, Gendelman and colleagues (Reynolds et al, 2010) have suggested that the Syn-specific regulatory T-cells (Treg cells), which are regulatory components of the adaptive immunity, might be able to counteract the autoaggresive effector T-cell responses that exacerbate neuroinflammation (Benner et al, 2008), and therefore contribute to attenuate neurodegeneration in PD. Indeed, the same group has reported that microglial cells stimulated with N-Syn are susceptible of essentially opposing immune regulatory responses by Treg cells (CD4 + , CD245 + ) and effector T-cells (CD4 + , CD25 -) in culture (Reynolds et al, 2009a). By analysing an array of cytokines released by treated microglia, the authors found that, while the effector T-cell subset exacerbates microglial-mediated inflammation and may induce neurotoxic responses, Treg cells are able to suppress N-Syn microglial-induced reactive-oxygen species (ROS) and NF-B activation and are proposed to be neuroprotective (Reynolds et al, 2009a).…”

“…Indeed, the same group has reported that microglial cells stimulated with N-Syn are susceptible of essentially opposing immune regulatory responses by Treg cells (CD4 + , CD245 + ) and effector T-cells (CD4 + , CD25 -) in culture (Reynolds et al, 2009a). By analysing an array of cytokines released by treated microglia, the authors found that, while the effector T-cell subset exacerbates microglial-mediated inflammation and may induce neurotoxic responses, Treg cells are able to suppress N-Syn microglial-induced reactive-oxygen species (ROS) and NF-B activation and are proposed to be neuroprotective (Reynolds et al, 2009a). Furthermore, the study indicates that Treg cells can regulate microglial inflammation by inducing Fas-FasL-mediated apoptosis of NSyn-stimulated microglial cells (Reynolds et al, 2009a).…”

Role of Microglia in Inflammatory Process in Parkinson’s Disease

“…The transfer of T cells from mice immunized with nitrated α-synuclein into MPTPtreated mice caused significant infiltration into the brain and a neuroinflammatory response with accelerated dopaminergic neuron loss (Benner et al, 2008). The consequence of two subsets of CD4 + lymphocytes that acted on microglia was reported to be different (Reynolds et al, 2009). In the presence of nitrated α-synuclein, one subset, i.e., CD4 + CD25 -(effector) T cells, enhanced the microglial activation and neurotoxic responses by secreting TNF-α and IFN-γ;and the other, CD4 + CD25 + (regulatory) T cells, suppressed the microglia activation and induced microglia apoptosis by secreting IL-10 and TGF-β.…”