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Emerging evidence has demonstrated that CD4+ T cells infiltrate into the substantia nigra (SN) in Parkinson's disease (PD) patients and in animal models of PD. SN-infiltrated CD4+ T cells bearing inflammatory phenotypes promote microglial activation and strongly contribute to neurodegeneration of dopaminergic neurons. Importantly, altered expression of dopamine receptor D3 (D3R) in PBLs from PD patients has been correlated with disease severity. Moreover, pharmacological evidence has suggested that D3R is involved in IFN-γ production by human CD4+ T cells. In this study, we examined the role of D3R expressed on CD4+ T cells in neurodegeneration of dopaminergic neurons in the SN using a mouse model of PD. Our results show that D3R-deficient mice are strongly protected against loss of dopaminergic neurons and microglial activation during 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. Notably, D3R-deficient mice become susceptible to MPTP-induced neurodegeneration and microglial activation upon transfer of wild-type (WT) CD4+ T cells. Furthermore, RAG1 knockout mice, which are devoid of T cells and are resistant to MPTP-induced neurodegeneration, become susceptible to MPTP-induced loss of dopaminergic neurons when reconstituted with WT CD4+ T cells but not when transferred with D3R-deficient CD4+ T cells. In agreement, experiments analyzing activation and differentiation of CD4+ T cells revealed that D3R favors both T cell activation and acquisition of the Th1 inflammatory phenotype. These findings indicate that D3R expressed on CD4+ T cells plays a fundamental role in the physiopathology of MPTP-induced PD in a mouse model.

Dendritic cells (DCs) are responsible for priming T cells and for promoting their differentiation from naive T cells into appropriate effector cells. Emerging evidence suggests that neurotransmitters can modulate T cell-mediated immunity. However, the involvement of specific neurotransmitters or receptors remains poorly understood. In this study, we analyzed the role of dopamine in the regulation of DC function. We found that DCs express dopamine receptors as well as the machinery necessary to synthesize, store, and degrade dopamine. Notably, the expression of D5R decreased upon LPS-induced DC maturation. Deficiency of D5R on the surface of DCs impaired LPS-induced IL-23 and IL-12 production and consequently attenuated the activation and proliferation of Ag-specific CD4+ T cells. To determine the relevance of D5R expressed on DCs in vivo, we studied the role of this receptor in the modulation of a CD4+ T cell-driven autoimmunity model. Importantly, D5R-deficient DCs prophylactically transferred into wild-type recipients were able to reduce the severity of experimental autoimmune encephalomyelitis. Furthermore, mice transferred with D5R-deficient DCs displayed a significant reduction in the percentage of Th17 cells infiltrating the CNS without differences in the percentage of Th1 cells compared with animals transferred with wild-type DCs. Our findings demonstrate that by contributing to CD4+ T cell activation and differentiation to Th17 phenotype, D5R expressed on DCs is able to modulate the development of an autoimmune response in vivo.

Dopamine receptor D3 (DRD3) expressed on CD4+ T cells is required to promote neuroinflammation in a murine model of Parkinson’s disease. However, how DRD3 signaling affects T cell–mediated immunity remains unknown. In this study, we report that TCR stimulation on mouse CD4+ T cells induces DRD3 expression, regardless of the lineage specification. Importantly, functional analyses performed in vivo using adoptive transfer of OVA-specific OT-II cells into wild-type recipients show that DRD3 deficiency in CD4+ T cells results in attenuated differentiation of naive CD4+ T cells toward the Th1 phenotype, exacerbated generation of Th2 cells, and unaltered Th17 differentiation. The reciprocal regulatory effect of DRD3 signaling in CD4+ T cells favoring Th1 generation and impairing the acquisition of Th2 phenotype was also reproduced using in vitro approaches. Mechanistic analysis indicates that DRD3 signaling evokes suppressor of cytokine signaling 5 expression, a negative regulator of Th2 development, which indirectly favors acquisition of Th1 phenotype. Accordingly, DRD3 deficiency results in exacerbated eosinophil infiltration into the airways of mice undergoing house dust mite–induced allergic response. Interestingly, our results show that, upon chronic inflammatory colitis induced by transfer of naive CD4+ T cells into lymphopenic recipients, DRD3 deficiency not only affects Th1 response, but also the frequency of Th17 cells, suggesting that DRD3 signaling also contributes to Th17 expansion under chronic inflammatory conditions. In conclusion, our findings indicate that DRD3-mediated signaling in CD4+ T cells plays a crucial role in the balance of effector lineages, favoring the inflammatory potential of CD4+ T cells.

Parkinson's disease (PD) is a neurodegenerative disorder affecting mainly the dopaminergic neurons of the nigrostriatal pathway, a neuronal circuit involved in the control of movements, thereby the main manifestations correspond to motor impairments. The major molecular hallmark of this disease corresponds to the presence of pathological protein inclusions called Lewy bodies in the midbrain of patients, which have been extensively associated with neurotoxic effects. Importantly, different research groups have demonstrated that CD4 + T-cells infiltrate into the substantia nigra of PD patients and animal models. Moreover, several studies have consistently demonstrated that T-cell deficiency results in a strong attenuation of dopaminergic neurodegeneration in animal models of PD, thus indicating a key role of adaptive immunity in the neurodegenerative process. Recent evidence has shown that CD4 + T-cell response involved in PD patients is directed to oxidised forms of α-synuclein, one of the main constituents of Lewy bodies. On the other hand, most PD patients present a number of non-motor manifestations. Among non-motor manifestations, gastrointestinal dysfunctions result especially important as potential early biomarkers of PD, since they are ubiquitously found among confirmed patients and occur much earlier than motor symptoms. These gastrointestinal dysfunctions include constipation and inflammation of the gut mucosa and the most distinctive pathologic features associated are the loss of neurons of the enteric nervous system and the generation of Lewy bodies in the gut. Moreover, emerging evidence has recently shown a pivotal role of gut microbiota in triggering the development of PD in genetically predisposed individuals. Of note, PD has been positively correlated with inflammatory bowel diseases, a group of disorders involving a T-cell driven inflammation of gut mucosa, which is strongly dependent in the composition of gut microbiota. Here we raised the hypothesis that T-cell driven inflammation, which mediates dopaminergic neurodegeneration in PD, is triggered in the gut mucosa. Accordingly, we discuss how structural components of commensal bacteria or how different mediators produced by gut-microbiota, including short-chain fatty acids and dopamine, may affect the behaviour of T-cells, triggering the development of T-cell responses against Lewy bodies, initially confined to the gut mucosa but later extended to the brain.

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BackgroundNeuroinflammation constitutes a pathogenic process leading to neurodegeneration in several disorders, including Alzheimer’s disease, Parkinson’s disease (PD) and sepsis. Despite microglial cells being the central players in neuroinflammation, astrocytes play a key regulatory role in this process. Our previous results indicated that pharmacologic-antagonism or genetic deficiency of dopamine receptor D3 (DRD3) attenuated neuroinflammation and neurodegeneration in two mouse models of PD. Here, we studied how DRD3-signalling affects the dynamic of activation of microglia and astrocyte in the context of systemic inflammation.MethodsNeuroinflammation was induced by intraperitoneal administration of LPS. The effect of genetic DRD3-deficiency or pharmacologic DRD3-antagonism in the functional phenotype of astrocytes and microglia was determined by immunohistochemistry and flow cytometry at different time-points.ResultsOur results show that DRD3 was expressed in astrocytes, but not in microglial cells. DRD3 deficiency resulted in unresponsiveness of astrocytes and in attenuated microglial activation upon systemic inflammation. Furthermore, similar alterations in the functional phenotypes of glial cells were observed by DRD3 antagonism and genetic deficiency of DRD3 upon LPS challenge. Mechanistic analyses show that DRD3 deficiency resulted in exacerbated expression of the anti-inflammatory protein Fizz1 in glial cells both in vitro and in vivo.ConclusionsThese results suggest that DRD3 signalling regulates the dynamic of the acquisition of pro-inflammatory and anti-inflammatory features by astrocytes and microglia, finally favouring microglial activation and promoting neuroinflammation.

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