title: 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.
authors.affiliation: Laboratorio de Neuroinmunología, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile.
authors.forename: Hugo
authors.initials: H
authors.lastname: González
authors.forename: Francisco
authors.initials: F
authors.lastname: Contreras
authors.forename: Carolina
authors.initials: C
authors.lastname: Prado
authors.forename: Daniela
authors.initials: D
authors.lastname: Elgueta
authors.forename: Dafne
authors.initials: D
authors.lastname: Franz
authors.forename: Sebastián
authors.initials: S
authors.lastname: Bernales
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Pacheco
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000276:immunology / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics*; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D050637:Receptors, Dopamine D3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D013154:Spleen; D013378:Substantia Nigra / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C493594:Drd3 protein, mouse; D018398:Homeodomain Proteins; D050637:Receptors, Dopamine D3; D014409:Tumor Necrosis Factor-alpha; C064658:RAG-1 protein; D007371:Interferon-gamma; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine