title: Granzyme B mediates neurotoxicity through a G-protein-coupled receptor.
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 Gialpha 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 1alpha. 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.
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Tongguang
authors.initials: T
authors.lastname: Wang
authors.forename: Rameeza
authors.initials: R
authors.lastname: Allie
authors.forename: Katherine
authors.initials: K
authors.lastname: Conant
authors.forename: Norman
authors.initials: N
authors.lastname: Haughey
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Turchan-Chelowo
authors.forename: Katrin
authors.initials: K
authors.lastname: Hahn
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
authors.forename: Joseph
authors.initials: J
authors.lastname: Steiner
authors.forename: Sanjay
authors.initials: S
authors.lastname: Keswani
authors.forename: Melina
authors.initials: M
authors.lastname: Jones
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D053804:Granzymes; D006801:Humans; D008213:Lymphocyte Activation; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism / Q000633:toxicity*; D013601:T-Lymphocytes / Q000201:enzymology*
chemical_list: D000975:Antioxidants; D002839:Chromans; C104949:GPI 1046; D011759:Pyrrolidines; D043562:Receptors, G-Protein-Coupled; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D020169:Caspases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D002118:Calcium