期刊
FASEB JOURNAL
卷 20, 期 8, 页码 1209-+出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.05-5022fje
关键词
T cell; multiple sclerosis; pertussis toxin; cAMP; caspase-3; immune reconstitution syndrome
资金
- NIMH NIH HHS [P01MH070056] Funding Source: Medline
- NINDS NIH HHS [R01NS039253, R01NS043990] Funding Source: Medline
Neuroinflammatory diseases such as multiple sclerosis ( MS) are characterized by focal regions of demyelination and axonal loss associated with infiltrating T cells. However, the role of activated T cells in causing neuronal injury remains unclear. CD4 and CD8 T cells were isolated from normal donors and polyclonally activated using plate-bound anti-CD3 and soluble anti-CD28. The conditioned T cell supernatants caused toxicity to cultured human fetal neurons, which could be blocked by immunodepleting the supernatants of granzyme B (GrB). Recombinant GrB also caused toxicity in neurons by caspase-dependent pathways but no toxicity was seen in astrocytes. The neurotoxicity was independent of perforin and could not be blocked by mannose-6-phosphate. However, GrB-induced neurotoxicity was sensitive to pertussis toxin, implicating the stimulation of Gi alpha protein-coupled receptors. GrB caused a decrease in cAMP levels but only modest increases in intracellular calcium. The effect on intracellular calcium could be markedly potentiated by stromal-derived factor 1 alpha. GrB-induced neurotoxicity could also be blocked by vitamin E and a neuroimmunophilin ligand. In conclusion, GrB may be an important mediator of neuronal injury in T cell-mediated neuroinflammatory disorders.
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