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Granzyme B mediates neurotoxicity through a G-protein-coupled receptor

Tongguang Wang^*, Rameeza Allie^*, Katherine Conant^*, Norman Haughey^*, Jadwiga Turchan-Chelowo, Katrin Hahn^*, Antony Rosen, Joseph Steiner^*, Sanjay Keswani^*, Melina Jones^*, Peter A. Calabresi^* and Avindra Nath^*,1

^* Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA;

Department of Internal Medicine, Johns Hopkins University, Baltimore, Maryland, USA; and

Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, USA

¹Correspondence: Department of Neurology, Pathology Bldg. Rm. 509, 600 N. Wolfe St., Baltimore, MD 21287, USA. E-Mail: anath1{at}jhmi.edu

ABSTRACT

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 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. 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.—Wang, T., Allie, R., Conant, K., Haughey, N., Turchan-Chelowo, J., Hahn, K., Rosen, A., Steiner, J., Keswani, S., Jones, M., Calabresi, P. A., and Nath, A. Granzyme B mediates neurotoxicity through a G-protein coupled receptor.

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