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