Generation of NO by bystander human CD8 T cells augments allogeneic responses by inhibiting cytokine deprivation-induced cell death

Am J Transplant. 2009 Oct;9(10):2281-91. doi: 10.1111/j.1600-6143.2009.02771.x. Epub 2009 Aug 6.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Bystander Effect*
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Caspase Inhibitors
  • Cell Death*
  • Cell Proliferation
  • Cells, Cultured
  • Cyclic GMP / metabolism
  • Cytokines / metabolism*
  • Humans
  • Immunoprecipitation
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide / physiology
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Signal Transduction

Substances

  • Caspase Inhibitors
  • Cytokines
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Cyclic GMP