Abstract
BackgroundNeural-antigen reactive cytotoxic CD8+ T cells contribute to neuronal dysfunction and degeneration in a variety of inflammatory CNS disorders. Facing excess numbers of target cells, CNS-invading CD8+ T cells cause neuronal cell death either via confined release of cytotoxic effector molecules towards neurons, or via spillover of cytotoxic effector molecules from 'leaky’ immunological synapses and non-confined release by CD8+ T cells themselves during serial and simultaneous killing of oligodendrocytes or astrocytes.MethodsWild-type and T cell receptor transgenic CD8+ T cells were stimulated in vitro, their activation status was assessed by flow cytometry, and supernatant glutamate levels were determined using an enzymatic assay. Expression regulation of molecules involved in vesicular glutamate release was examined by quantitative real-time PCR, and mechanisms of non-vesicular glutamate release were studied by pharmacological blocking experiments. The impact of CD8+ T cell-mediated glutamate liberation on neuronal viability was studied in acute brain slice preparations.ResultsFollowing T cell receptor stimulation, CD8+ T cells acquire the molecular repertoire for vesicular glutamate release: (i) they upregulate expression of glutaminase required to generate glutamate via deamination of glutamine and (ii) they upregulate expression of vesicular proton-ATPase and vesicular glutamate transporters required for filling of vesicles with glutamate. Subsequently, CD8+ T cells release glutamate in a strictly stimulus-dependent manner. Upon repetitive T cell receptor stimulation, CD25high CD8+ T effector cells exhibit higher estimated single cell glutamate release rates than CD25low CD8+ T memory cells. Moreover, glutamate liberation by oligodendrocyte-reactive CD25high CD8+ T effector cells is capable of eliciting collateral excitotoxic cell death of neurons (despite glutamate re-uptake by glia cells and neurons) in intact CNS gray matter.ConclusionGlutamate release may represent a crucial effector pathway of neural-antigen reactive CD8+ T cells, contributing to excitotoxicity in CNS inflammation.
Highlights
Cytotoxic CD8+ T cells directed against neuronal or glial antigens contribute to neuronal cell death in a variety of inflammatory CNS disorders [1,2,3]
We have shown that activated T cell receptor (TCR)-transgenic, ovalbumin (OVA)-reactive CD8+ T cells (OT-I cells [5]) are capable of initiating ‘collateral’ neuronal apoptosis in the gray matter of otherwise non-inflamed acute brain slices from ODC-OVA mice selectively expressing OVA in ODCs under the control of a truncated myelin basic protein (MBP)-promotor
None of the tested blockers of non-vesicular glutamate release mechanisms significantly reduced supernatant glutamate levels after 72 hours of CD8+ T cell beadstimulation
Summary
Cytotoxic CD8+ T cells directed against neuronal or glial antigens contribute to neuronal cell death in a variety of inflammatory CNS disorders [1,2,3]. They are capable of harming neuronal function and integrity either by directly targeting neurons and their neurites or by exerting. The T cell-derived glutamate elicits the release of thiols (cysteine, glutathione and cysteinyl-glycine) and lactate from astrocytes, which reduce neuronal apoptosis induced by oxidative stress [11]. Neural-antigen reactive cytotoxic CD8+ T cells contribute to neuronal dysfunction and degeneration in a variety of inflammatory CNS disorders. Facing excess numbers of target cells, CNS-invading CD8+ T cells cause neuronal cell death either via confined release of cytotoxic effector molecules towards neurons, or via spillover of cytotoxic effector molecules from ‘leaky’ immunological synapses and non-confined release by CD8+ T cells themselves during serial and simultaneous killing of oligodendrocytes or astrocytes
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