Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease
Vanessa Brochard, Béhazine Combadière, Annick Prigent, Yasmina Laouar, Aline Perrin, Virginie Beray-Berthat, Olivia Bonduelle, Daniel Alvarez-Fischer, Jacques Callebert, Jean-Marie Launay, Charles Duyckaerts, Richard A. Flavell, Etienne C. Hirsch, Stéphane Hunot
Vanessa Brochard, Béhazine Combadière, Annick Prigent, Yasmina Laouar, Aline Perrin, Virginie Beray-Berthat, Olivia Bonduelle, Daniel Alvarez-Fischer, Jacques Callebert, Jean-Marie Launay, Charles Duyckaerts, Richard A. Flavell, Etienne C. Hirsch, Stéphane Hunot
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Research Article

Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease

Abstract

Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1–/– and Tcrb–/– mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1–/– mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1–/– mice reconstituted with IFN-γ–deficient splenocytes were not protected. These data indicate that T cell–mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells and requires the expression of FasL but not IFNγ. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.

Authors

Vanessa Brochard, Béhazine Combadière, Annick Prigent, Yasmina Laouar, Aline Perrin, Virginie Beray-Berthat, Olivia Bonduelle, Daniel Alvarez-Fischer, Jacques Callebert, Jean-Marie Launay, Charles Duyckaerts, Richard A. Flavell, Etienne C. Hirsch, Stéphane Hunot

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Figure 2

MPTP-induced nigrostriatal pathway injury stimulates T cell brain infiltration in mouse.

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MPTP-induced nigrostriatal pathway injury stimulates T cell brain infilt...
(A) Schematic representation of the experimental approach (see Methods). The green circle within reconstituted mice refers to the lymphoid compartments replenished with GFP+ cells. (B) GFP+ T cell infiltration in the SNpc and (C) striatum following MPTP intoxication. Numerous GFP+ T cells can be seen in the SNpc 2 days after MPTP but not saline exposure. GFP+ T cells are also found in the striatum from intoxicated mice, though there are far fewer than in the SNpc. Scale bars: 300 μm (B); 100 μm (C); 10 μm (insets). (D) Immunofluorescent staining for TH, Glut1, CD8, or CD4. Note that infiltrated GFP+ T cells are clustered within the SNpc in close proximity to TH+ DNs. Transmigrated GFP+ T cells are not found in the lumen of Glut1+ blood vessels (arrows) and consist of both CD8+ and CD4+ T cell subsets. Scale bars: 20 μm. (E) T cell brain infiltration in MPTP-treated C57BL/6 inbred mice. CD3 immunostaining showing numerous T lymphocytes within the SNpc (dashed line) from MPTP-treated mice (left panel). Scale bar: 100 μm. Kinetic of nigral CD4+ and CD8+ T cell (insets) density after MPTP exposure (right panel). S, saline. Data points represent the mean ± SEM. *P < 0.01 compared with saline- and MPTP-treated mice at day 4 after MPTP exposure; †P < 0.01 compared with saline-treated controls (Tukey post-hoc analysis). Scale bars: 50 μm. (F) Double immunofluorescence staining for PCNA and GFP and GFAP or Mac1. Note that PCNA+ cells in the SNpc never colocalize with GFP+ or GFAP+ cells, whereas they superpose perfectly with Mac-1+ macrophages/microglial cells (arrows). Scale bar: 50 μm.