Granzyme B mediates neurotoxicity through a G-protein-coupled receptor.
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.
Wang
Tongguang
T
Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.
Allie
Rameeza
R
Conant
Katherine
K
Haughey
Norman
N
Turchan-Chelowo
Jadwiga
J
Hahn
Katrin
K
Rosen
Antony
A
Steiner
Joseph
J
Keswani
Sanjay
S
Jones
Melina
M
Calabresi
Peter A
PA
Nath
Avindra
A
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*
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