Generation of NO by bystander human CD8 T cells augments allogeneic responses by inhibiting cytokine deprivation-induced cell death.
Nitric oxide (NO), generated by inducible NO synthase (iNOS) in bystander human CD8 T cells, augments the accumulation of allogeneically activated human CD8 T cells in vitro and in vivo. Here, we report that iNOS-derived NO does not affect T-cell proliferation but rather inhibits cell death of activated human CD8 T cells after activation by allogeneic endothelial cells in culture. Exogenous NO did not affect activation-induced cell death of human CD8 T cells but specifically reduced death of activated T cells due to cytokine deprivation. NO-mediated inhibition of T-cell death did not involve cGMP signaling, and NO did not affect the expression of Bcl-2-related proteins known to regulate cytokine deprivation-induced cell death. However, NO inhibited the activity of caspases activated as a consequence of cytokine deprivation in activated T cells. This protective effect correlated with S-nitrosylation of caspases and was phenocopied by z-VAD.fmk and z-LEHD.fmk, pharmacological inhibitors of caspases. In summary, our findings indicate that NO augments the accumulation of activated human T cells principally by inhibiting cytokine deprivation-induced cell death through S-nitrosylation of caspases.
Choy
J C
JC
Section of Human and Translational Immunology, Yale University School of Medicine, New Haven, CT, USA.
Pober
J S
JS
D015153:Blotting, Western; D024201:Bystander Effect; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D061945:Caspase Inhibitors; D016923:Cell Death; D049109:Cell Proliferation; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D015398:Signal Transduction
D061945:Caspase Inhibitors; D016207:Cytokines; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D006152:Cyclic GMP