Death or survival: Membrane ceramide controls the fate and activation of antigen-specific T-cells depending on signal strength and duration

摘要: Abstract Sphingomyelinase (SMase)-mediated release of ceramide in the plasma membrane T-lymphocytes induced by different stimuli such as ligation Fas/CD95, irradiation, stress, inflammation or anticancer drugs primarily involves mitochondrial apoptosis signaling, but under specific conditions non-apoptotic Fas-signaling was also reported. Here we investigated, using a quantitative simulation model with exogenous C2-ceramide (and SMase), dependence activation and fate T-cells on strength duration accumulation. A murine, influenza virus hemagglutinin-specific T-helper cell (IP12-7) alone together interacting antigen presenting B-cells (APC) used. T H cells above ‘threshold’ stimulus (> 25 μM ‘strength’ > 30 min duration), while below threshold non-apoptotic, confirmed early late apoptotic markers (PS-translocation, depolarization, caspase-3 activation, DNA-fragmentation). The modest strongly suppressed calcium response inhibited several downstream signal events (e.g. ERK1/2-, JNK-phosphorylation, CD69 expression IL-2 production) during both anti-CD3 APC-triggered activation. Ceramide moderately affected Ca 2+ -release from internal stores upon antigen-specific engagement TCR immunological synapses, influx phase remarkably reduced amplitude rate, suggesting that major target(s) ceramide-effects are membrane-proximal. Kv1.3 potassium channels, store operated -entry (SOC) depolarized to which contribution spontaneously formed channels is possible. impaired function these transporters may be coupled quantitative, raft-remodeling effect responsible, concerted action, for Our results suggest Fas stimuli, received previously activated, FasL+ lymphocytes lymph nodes, negatively regulate subsequent T-cell thus modulate response.