Death or survival: membrane ceramide controls the fate and activation of antigen-specific T-cells depending on signal strength and duration |
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| Authors: | Detre Cynthia Kiss Endre Varga Zoltán Ludányi Katalin Pászty Katalin Enyedi Agnes Kövesdi Dorottya Panyi György Rajnavölgyi Eva Matkó János |
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| Affiliation: | 1. Department of Immunology, Eötvös Lorand University, Pázmány P. sétány 1/C, 1117, Budapest, Hungary;2. Department of Immunology, University of Debrecen, Health Science Center, Debrecen, Hungary;3. Department of Biophysics and Cell Biology, University of Debrecen, Health Science Center, Debrecen, Hungary;4. National Institute of Haematology and Immunology, Budapest, Hungary;3. Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio 44195;4. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195;1. University of Pennsylvania, Philadelphia, PA, USA;2. Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA;3. Eastern Washington University, Cheney, WA, USA;1. Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA;2. Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA;1. Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53711, USA;2. Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan;1. Department of Pediatric Urology, Hôpital Femme, Mère, Enfant, 59 Boulevard Pinel, 69677 Bron, France;2. Department of Urology and Pediatric Urology, Cliniques universitaires Saint Luc, 10 Avenue Hippocrate, 1200 Woluwé, Belgium;1. Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea;2. Laboratory of Clinical and Epidemiological Virology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium;3. Bioindustry Research Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 580-185, Republic of Korea;4. Chonnam National University Veterinary Teaching Hospital, Gwangju 500-757, Republic of Korea;5. Division of Life Science, Korea Basic Science Institute, Daejeon 305-806, Republic of Korea |
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| Abstract: | Sphingomyelinase (SMase)-mediated release of ceramide in the plasma membrane of T-lymphocytes induced by different stimuli such as ligation of 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), the dependence of activation and fate of T-cells on the strength and duration of ceramide accumulation. A murine, influenza virus hemagglutinin-specific T-helper cell (IP12-7) alone or together with interacting antigen presenting B-cells (APC) was used. C2-ceramide induced apoptosis of TH cells above a 'threshold' stimulus (>25 microM in 'strength' or >30 min in duration), while below the threshold C2-ceramide was non-apoptotic, as confirmed by early and late apoptotic markers (PS-translocation, mitochondrial depolarization, caspase-3 activation, DNA-fragmentation). The modest ceramide stimuli strongly suppressed the calcium response and inhibited several downstream signal events (e.g. ERK1/2-, JNK-phosphorylation, CD69 expression or IL-2 production) in TH cells during both anti-CD3 induced and APC-triggered activation. Ceramide moderately affected the Ca2+ -release from internal stores upon antigen-specific engagement of TCR in immunological synapses, while the influx phase was remarkably reduced in both amplitude and rate, suggesting that the major target(s) of ceramide-effects are membrane-proximal. Ceramide inhibited Kv1.3 potassium channels, store operated Ca2+ -entry (SOC) and depolarized the plasma membrane to which contribution of spontaneously formed ceramide channels is possible. The impaired function of these transporters may be coupled to the quantitative, membrane raft-remodeling effect of ceramide and responsible, in a concerted action, for the suppressed activation. Our results suggest that non-apoptotic Fas stimuli, received from previously activated, FasL+ interacting lymphocytes in the lymph nodes, may negatively regulate subsequent antigen-specific T-cell activation and thus modulate the antigen-specific T-cell response. |
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