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- Title
Cytotoxic CD8<sup>+</sup> T Cell-Neuron Interactions: Perforin-Dependent Electrical Silencing Precedes But Is Not Causally Linked to Neuronal Cell Death.
- Authors
Meuth, Sven G.; Herrmann, Alexander M.; Simon, Ole J.; Siffrin, Volker; Melzer, Nico; Bittner, Stefan; Meuth, Patrick; Langer, Harald F.; Hallermann, Stefan; Boldakowa, Nadia; Herz, Josephine; Munsch, Thomas; Landgraf, Peter; Aktas, Orhan; Heckmann, Manfred; Lessmann, Volkmar; Budde, Thomas; Kieseier, Bernd C.; Zipp, Frauke; Wiendl, Heinz
- Abstract
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 Ca2+ levels (within <10 min). (2) Antigen-dependent neuronal apoptosis may occur independently of perforin and members of the granzyme B cluster (within ∼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.
- Subjects
CELL-mediated cytotoxicity; T cell receptors; VIDEO microscopy; PHOTONS; APOPTOSIS; NEURONS
- Publication
Journal of Neuroscience, 2009, Vol 29, Issue 49, p15397
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.4339-09.2009