Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease.
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.
Brochard
Vanessa
V
INSERM, UMR S679, Experimental Neurology and Therapeutics, Hopital de la Salpetriere, Paris, France.
Combadière
Béhazine
B
Prigent
Annick
A
Laouar
Yasmina
Y
Perrin
Aline
A
Beray-Berthat
Virginie
V
Bonduelle
Olivia
O
Alvarez-Fischer
Daniel
D
Callebert
Jacques
J
Launay
Jean-Marie
JM
Duyckaerts
Charles
C
Flavell
Richard A
RA
Hirsch
Etienne C
EC
Hunot
Stéphane
S
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000276:immunology / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000276:immunology / Q000473:pathology; D020734:Parkinsonian Disorders / Q000276:immunology / Q000473:pathology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D018398:Homeodomain Proteins; C064658:RAG-1 protein; D007371:Interferon-gamma; D004298:Dopamine