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

Meuth, S.G.; Herrmann, A.M.; Simon, O.J.; Siffrin, V.; Melzer, N.; Bittner, S.; Meuth, P.; Langer, H.F.; Hallermann, S.; Boldakowa, N.; Herz, J.; Munsch, T.; Landgraf, P.; Aktas, O.; Heckmann, M.; Lessmann, V.; Budde, T.; Kieseier, B.C.; Zipp, F.; Wiendl, H.

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

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Item Type:	Article
Title:	Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death
Creators Name:	Meuth, S.G., Herrmann, A.M., Simon, O.J., Siffrin, V., Melzer, N., Bittner, S., Meuth, P., Langer, H.F., Hallermann, S., Boldakowa, N., Herz, J., Munsch, T., Landgraf, P., Aktas, O., Heckmann, M., Lessmann, V., Budde, T., Kieseier, B.C., Zipp, F. and Wiendl, H.
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 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.
Keywords:	CD8 Antigens, Calcium, Cell Communication, Cell Death, Cell Movement, Cultured Cells, Electric Capacitance, MHC Class I Genes, Granzymes, Hippocampus, Intracellular Space, Membrane Potentials, Neural Pathways, Neurons, Perforin, T-Lymphocytes, Time Factors, Animals, Mice
Source:	Journal of Neuroscience
ISSN:	0270-6474
Publisher:	Society for Neuroscience
Volume:	29
Number:	49
Page Range:	15397-15409
Date:	9 December 2009
Additional Information:	Copyright (c) 2009 by The Society for Neuroscience
Official Publication:	https://doi.org/10.1523/JNEUROSCI.4339-09.2009
PubMed:	View item in PubMed

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