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, Avindra Nath

Research output: Contribution to journalArticle

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 Giα 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 1α. 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.

Original languageEnglish (US)
Pages (from-to)E390-E398
JournalFASEB Journal
Volume20
Issue number8
DOIs
StatePublished - Jun 1 2006

Keywords

  • Caspase-3
  • Immune reconstitution syndrome
  • Multiple sclerosis
  • Pertussis toxin
  • T cell
  • cAMP

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'Granzyme B mediates neurotoxicity through a G-protein-coupled receptor'. Together they form a unique fingerprint.

  • Cite this

    Wang, T., Allie, R., Conant, K., Haughey, N., Turchan-Chelowo, J., Hahn, K., Rosen, A., Steiner, J., Keswani, S., Jones, M., Calabresi, P. A., & Nath, A. (2006). Granzyme B mediates neurotoxicity through a G-protein-coupled receptor. FASEB Journal, 20(8), E390-E398. https://doi.org/10.1096/fj.05-5022fje