Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons duringparkinson's disease

Hugo González, Francisco Contreras, Carolina Prado, Daniela Elgueta, Dafne Franz, Sebastián Bernales, Rodrigo Pacheco

Resultado de la investigación: Article

71 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)5048-5056
Número de páginas9
PublicaciónJournal of Immunology
Volumen190
N.º10
DOI
EstadoPublished - 15 may 2013

Huella dactilar

Dopamine D3 Receptors
Dopaminergic Neurons
T-Lymphocytes
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Parkinson Disease
Substantia Nigra
Phenotype
Knockout Mice
Animal Models

ASJC Scopus subject areas

  • Immunology

Citar esto

González, H., Contreras, F., Prado, C., Elgueta, D., Franz, D., Bernales, S., & Pacheco, R. (2013). Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons duringparkinson's disease. Journal of Immunology, 190(10), 5048-5056. https://doi.org/10.4049/jimmunol.1203121
González, Hugo ; Contreras, Francisco ; Prado, Carolina ; Elgueta, Daniela ; Franz, Dafne ; Bernales, Sebastián ; Pacheco, Rodrigo. / Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons duringparkinson's disease. En: Journal of Immunology. 2013 ; Vol. 190, N.º 10. pp. 5048-5056.
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title = "Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons duringparkinson'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.",
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González, H, Contreras, F, Prado, C, Elgueta, D, Franz, D, Bernales, S & Pacheco, R 2013, 'Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons duringparkinson's disease', Journal of Immunology, vol. 190, n.º 10, pp. 5048-5056. https://doi.org/10.4049/jimmunol.1203121

Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons duringparkinson's disease. / González, Hugo; Contreras, Francisco; Prado, Carolina; Elgueta, Daniela; Franz, Dafne; Bernales, Sebastián; Pacheco, Rodrigo.

En: Journal of Immunology, Vol. 190, N.º 10, 15.05.2013, p. 5048-5056.

Resultado de la investigación: Article

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T1 - Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons duringparkinson's disease

AU - González, Hugo

AU - Contreras, Francisco

AU - Prado, Carolina

AU - Elgueta, Daniela

AU - Franz, Dafne

AU - Bernales, Sebastián

AU - Pacheco, Rodrigo

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