Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death

J Neurosci. 2009 Dec 9;29(49):15397-409. doi: 10.1523/JNEUROSCI.4339-09.2009.


Cytotoxic CD8(+) T cells are considered important effector cells contributing to neuronal damage in inflammatory and degenerative CNS disorders. Using time-lapse video microscopy and two-photon imaging in combination with whole-cell patch-clamp recordings, we here show that major histocompatibility class I (MHC I)-restricted neuronal antigen presentation and T cell receptor specificity determine CD8(+) T-cell locomotion and neuronal damage in culture and hippocampal brain slices. Two separate functional consequences result from a direct cell-cell contact between antigen-presenting neurons and antigen-specific CD8(+) T cells. (1) An immediate impairment of electrical signaling in single neurons and neuronal networks occurs as a result of massive shunting of the membrane capacitance after insertion of channel-forming perforin (and probably activation of other transmembrane conductances), which is paralleled by an increase of intracellular Ca(2+) levels (within <10 min). (2) Antigen-dependent neuronal apoptosis may occur independently of perforin and members of the granzyme B cluster (within approximately 1 h), suggesting that extracellular effects can substitute for intracellular delivery of granzymes by perforin. Thus, electrical silencing is an immediate consequence of MHC I-restricted interaction of CD8(+) T cells with neurons. This mechanism is clearly perforin-dependent and precedes, but is not causally linked, to neuronal cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8 Antigens / metabolism*
  • Calcium / metabolism
  • Cell Communication / physiology*
  • Cell Death / physiology
  • Cell Movement / physiology
  • Cells, Cultured
  • Electric Capacitance
  • Genes, MHC Class I / physiology
  • Granzymes / genetics
  • Granzymes / metabolism
  • Hippocampus / physiology
  • In Vitro Techniques
  • Intracellular Space / physiology
  • Membrane Potentials / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Pathways / physiology
  • Neurons / physiology*
  • Perforin / genetics
  • Perforin / metabolism*
  • T-Lymphocytes / physiology*
  • Time Factors


  • CD8 Antigens
  • Perforin
  • Granzymes
  • Gzmb protein, mouse
  • Calcium