Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death.
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.
Meuth
Sven G
SG
Department of Neurology, University of Würzburg, D-97070 Würzburg, Germany. meuth_s@klinik.uni-wuerzburg.de
Herrmann
Alexander M
AM
Simon
Ole J
OJ
Siffrin
Volker
V
Melzer
Nico
N
Bittner
Stefan
S
Meuth
Patrick
P
Langer
Harald F
HF
Hallermann
Stefan
S
Boldakowa
Nadia
N
Herz
Josephine
J
Munsch
Thomas
T
Landgraf
Peter
P
Aktas
Orhan
O
Heckmann
Manfred
M
Lessmann
Volkmar
V
Budde
Thomas
T
Kieseier
Bernd C
BC
Zipp
Frauke
F
Wiendl
Heinz
H
D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D025802:Electric Capacitance; D005805:Genes, MHC Class I / Q000502:physiology; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D054353:Perforin / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology*; D013997:Time Factors
D016827:CD8 Antigens; D054353:Perforin; D053804:Granzymes; C509214:Gzmb protein, mouse; D002118:Calcium