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

Abstract

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.

Dopamine Receptor D3 Signaling on CD4+ T Cells Favors Th1- and Th17-Mediated Immunity

“…We have previously shown that activated Drd3 2/2 CD4 + T cells exhibit a slight impairment in IL-2 secretion compared with their WT counterparts (7,19). Accordingly, we next tested how DRD3 expression affects CD4 + T cell proliferation.…”

“…Given that CD4 + T cells not only play a key role in protecting the organism from various threats but are also potentially harmful to self-tissues, their function needs to be under stringent control. Dopamine (DA) is typically recognized for controlling complex processes such as locomotion, cognition, hormone secretion, renal function, and intestinal motility; however, recent evidence points to DA as a key regulator of the immune response involved in sepsis, autoimmune diseases, and neurodegenerative disorders (4)(5)(6)(7)(8). DA operates through engagement of five different DA receptors, termed DRD1-DRD5.…”

“…Interestingly, decreased DA levels are associated with inflammatory processes, such as neuroinflammation of the substantia nigra in the brain of Parkinson's disease patients and of the gut mucosa of inflammatory bowel disease patients (4). We have recently shown that genetic deficiency of the highest affinity DA receptor, dopamine receptor D3 (DRD3), on CD4 + T cells attenuates neuroinflammation and subsequent neurodegeneration on a murine model of Parkinson's disease (7). In line with this, pharmacologic stimulation of DRD3 in human T cells favors integrin activation and expression of IFN-g and TNF-a, whereas it reduces IL-4 and IL-10 production (12)(13)(14).…”

Dopamine Receptors and Neurodegeneration

“…Specialized patterns of adhesion of the cell surface during inflammation allow active T cells adhere to vessels and infiltrate to the brain, which contribute to neurodegenerative process [137,138]. In fact it has been shown that D3Rs expression in CD4 + T cells is crucial for the destruction of DA neurons of the SNc in PD models and the D3Rs knock out mice were resistant to MPTP [139], several evidences have shown that DA receptors expressed in immune cells play an important role in the autoimmune disorder MS.…”

Measures of Heart Rate Variability in Patients with Idiopathic Parkinson’s Disease

“…In terms of motor symptoms, postural instability, shaking, rigidity, and slowness of movements are the most common symptoms. There is loss of dopamine production in midbrain neurons, resulting in loss of dopaminergic innervations in the striatum [1]. In addition to an extra pyramidal motor dysfunction, patients frequently show Autonomic Nervous System (ANS) disorders, even in early phases of the disease [2].…”