IL-15 maintains T-cell survival via S-nitrosylation-mediated inhibition of caspase-3

Cell Death Differ. 2014 Jun;21(6):904-14. doi: 10.1038/cdd.2014.10. Epub 2014 Feb 7.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Caspase 3 / biosynthesis*
  • Caspase 3 / genetics
  • Cell Survival / genetics*
  • Glycolysis
  • Interleukin-15 / genetics
  • Interleukin-15 / metabolism*
  • Interleukin-2
  • Lymphocyte Activation / genetics
  • Mice
  • Mitochondria / metabolism
  • Signal Transduction
  • T-Lymphocytes / metabolism*

Substances

  • Interleukin-15
  • Interleukin-2
  • Caspase 3