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

Brochard, V., et al. 2009. J. Clin. Invest. 119, 182-192

Speaker: Yu-Ting Liao (廖郁婷)                                        Time: 14:10~15:00, Apr. 21, 2010

Commentator: Dr. Chiou-Feng Lin (林秋烽博士)    Place: Room 601

Abstract:

Parkinson disease (PD), a neurodegenerative disorder, results primarily from the death of dopamine-containing neurons (DNs) in the substantia nigra (SN). In the past four decades, PD medications mostly treat the symptoms, but treatments can’t effectively slow its progression.¹ In the previous studies, the infiltrated T cells highly express ICAM-1, IFA-1, and CD44 were found in Parkinson disease and MPTP-treated monkeys.² The PD-associated nitrotyrosine modification with α-synuclein promote an antigenic-specific response of peripheral T cells that could further affect microglial cell-dependent neurodegeneration.³ However, the role of the adaptive immunity in PD is still unclear. In this study, the authors found that both CD8⁺ and CD4⁺ T cells infiltrate the SN in the postmortem specimens of the PD’s patients. To reveal the functional mechanism of T lymphocyte infiltration, they implemented MPTP-intoxicated mouse model of PD. First, they used reconstituted mice which were replenished with GFP⁺ T or B cells in its lymphoid compartment. After MPTP treatment, brain sections showed that GFP⁺ T cells clustered in the vicinity of tyrosine hydrxylase (TH)-expressing DNs by TH immunostaining and extravasated by Glut1 immunostaining. They examined MPTP-associated blood-brain barrier disruption by testing serum albumin and immunoglobulin extravasation after MPTP administration and determined that a significant increase in ICAM-1 expression within the SN at the site of CD3⁺ T cell filtration. The CD3⁺ T cells express a marker of dividing cells, proliferating cell nuclear antigen (PCNA). Whereas the number of CD3⁺ T cell within the SN dramatically decrease after its accumulation at day 9 after treating MPTP. Furthermore, the results of double staining for CD3 and activated caspase-3, indicating the possibility that CD3⁺ T cell could be eliminated by apoptotic cell death. MPTP treatment in WT, Tcrb^-/-, Cd8a^-/-, and Cd4^-/- mice demonstrated that mice deficient in CD4⁺ T cells are more resistant to MPTP. In their disease model, the harmful lymphocyte response is CD4⁺ T cell-dependent. The Fas/FasL pathway, but not IFN-γ, is required for CD4⁺ T cell-mediated DN cell death. Collectively, the results provide a target in the adaptive immunity for therapeutic strategy in PD, but still have many unresolved parts should to be clarified.

References:

1.          Dauer, W., and Przedborski, S. 2003. Parkinson’s Disease: Mechanisms and Models. Neuron. 39, 889-909.

2.          Miklossy, J., et al. 2006. Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys. Exp. Neurol. 197, 275-283.

3.          Benner, E.J., et al. 2008. Nitrated α-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One. 3, e1376.