title: IL-15 maintains T-cell survival via S-nitrosylation-mediated inhibition of caspase-3.
abstract: Caspase activity is critical for both T-cell survival and death. However, little is known regarding what determines caspase activity in cycling T cells. Interleukin (IL)-2 and IL-15 confer very different susceptibilities to T-cell death. We therefore considered that IL-2 and IL-15 differentially regulate caspase activity to influence T-cell survival. We observed that IL-2-cultured primary murine effector T cells manifested elevated levels of caspase-3 activity compared with IL-15-cultured T cells. T cell receptor (TCR) restimulation further increased caspase activity and induced considerable cell death in IL-2-cultured T cells, but provoked only a minimal increase of caspase activity and cell death in IL-15-cultured T cells. IL-2 sensitization to cell death was caspase-3 mediated. Interestingly, increased active caspase-3 levels with IL-2 were independent of active initiator caspase-8 and caspase-9 that were similar with IL-2 and IL-15. Rather, caspase-3 activity was inhibited by posttranslational S-nitrosylation in IL-15-cultured T cells, but not in the presence of IL-2. This paralleled increased reactive nitrogen and oxygen species with IL-15 and reduced glycolysis. Taken together, these data suggest that the metabolic state conferred by IL-15 inhibits T-cell apoptosis in part by maintaining low levels of active caspase-3 via S-nitrosylation.
authors: Vermont Center for Immunology and Infectious Diseases, University of Vermont College of Medicine, Burlington, VT, USA.
authors: P T
authors: PT
authors: Saligrama
authors: Vermont Center for Immunology and Infectious Diseases, University of Vermont College of Medicine, Burlington, VT, USA.
authors: K A
authors: KA
authors: Fortner
authors: Vermont Center for Immunology and Infectious Diseases, University of Vermont College of Medicine, Burlington, VT, USA.
authors: M A
authors: MA
authors: Secinaro
authors: Vermont Center for Immunology and Infectious Diseases, University of Vermont College of Medicine, Burlington, VT, USA.
authors: C C
authors: CC
authors: Collins
authors: Vermont Center for Immunology and Infectious Diseases, University of Vermont College of Medicine, Burlington, VT, USA.
authors: J Q
authors: JQ
authors: Russell
authors: Vermont Center for Immunology and Infectious Diseases, University of Vermont College of Medicine, Burlington, VT, USA.
authors: R C
authors: RC
authors: Budd
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000096:biosynthesis* / Q000235:genetics; D002470:Cell Survival / Q000235:genetics*; D006019:Glycolysis; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D019409:Interleukin-15; D007376:Interleukin-2; D053148:Caspase 3