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

INSERM, UMR S679, Experimental Neurology and Therapeutics, Hopital de la Salpetriere, Paris, France.
Journal of Clinical Investigation (Impact Factor: 13.22). 01/2009; 119(1):182-92. DOI: 10.1172/JCI36470
Source: PubMed


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-gamma-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 IFNgamma. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.

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    • "Inflammatory processes are exacerbated in PD by the infiltration of peripheral immune cells such as T-lymphocytes, which are able to enter through the dysfunctional barrier and release pro-inflammatory cytokines, thereby further activating resident immune cells. Indeed, CD4 + and CD8 + T-cells have been observed within the SN in both the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD and at postmortem, with CD4 + T cells linked to MPTP-induced dopaminergic neurodegeneration (Brochard et al., 2009). The release of pro-inflammatory factors from either resident or peripheral immune cells may also directly increase BBB permeability by changing the expression of tight junction proteins (as reviewed by Hawkins and Davis, 2005) thereby allowing further infiltration of unwanted substances that could influence neurodegeneration. "

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    • "Both NM and α-syn are found extracellularly in the postmortem brain of PD patients (Double, 2012), a disorder that features high levels of activated microglia in the SN (Foix and Nicolesco, 1925) and high levels of intracellular oxidative stress (Fahn and Sulzer, 2004). Parkinson's disease patient brain features increased IFN-γ (Mogi et al., 2007) and chemokines (Harris et al., 2012), as well as a compromised blood brain barrier (Farkas et al., 2000; German et al., 2012) that may explain why CTLs are substantially higher in PD patients than age-matched controls (Hisanaga et al., 2001; Brochard et al., 2009). CD4+ T helper cells have also been shown to infiltrate the brain in human PD postmortem samples and exert a cytotoxic effect in mouse brain following nigrostriatal injury (Brochard et al., 2009); thus, T cells and antigen presentation, as well as activated microglia could play a role in PD pathogenesis. "
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    • "Since the invasion of T cells in the brain was first reported [58, 81], numerous studies have confirmed the infiltration of immune cells in the brain in both postmortem PD patients and animal models [82, 83]. These brain-invading lymphocytes consisted of a heterogeneous population of both CD8+ and CD4+ cells. "
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