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

FASEB J. 2006 Jun;20(8):1209-11. doi: 10.1096/fj.05-5022fje. Epub 2006 Apr 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Astrocytes / drug effects
  • Calcium / metabolism
  • Caspases / metabolism
  • Chromans / pharmacology
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Granzymes
  • Humans
  • Lymphocyte Activation
  • Neurons / drug effects*
  • Neurons / metabolism
  • Pyrrolidines / pharmacology
  • Receptors, G-Protein-Coupled / metabolism*
  • Serine Endopeptidases / metabolism
  • Serine Endopeptidases / toxicity*
  • T-Lymphocytes / enzymology*

Substances

  • Antioxidants
  • Chromans
  • GPI 1046
  • Pyrrolidines
  • Receptors, G-Protein-Coupled
  • GZMB protein, human
  • Granzymes
  • Serine Endopeptidases
  • Caspases
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
  • Calcium