Mechanisms of necroptosis in T cells

J Exp Med. 2011 Apr 11;208(4):633-41. doi: 10.1084/jem.20110251. Epub 2011 Mar 14.


Cell populations are regulated in size by at least two forms of apoptosis. More recently, necroptosis, a parallel, nonapoptotic pathway of cell death, has been described, and this pathway is invoked in the absence of caspase 8. In caspase 8-deficient T cells, necroptosis occurs as the result of antigen receptor-mediated activation. Here, through a genetic analysis, we show that necroptosis in caspase 8-deficient T cells is related neither to the programmed necrosis as defined by the requirement for mitochondrial cyclophilin D nor to autophagy as defined by the requirement for autophagy-related protein 7. Rather, survival of caspase 8-defective T cells can be completely rescued by loss of receptor-interacting serine-threonine kinase (Ripk) 3. Additionally, complementation of a T cell-specific caspase 8 deficiency with a loss of Ripk3 gives rise to lymphoproliferative disease reminiscent of lpr or gld mice. In conjunction with previous work, we conclude that necroptosis in antigen-stimulated caspase 8-deficient T cells is the result of a novel Ripk1- and Ripk3-mediated pathway of cell death.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis* / immunology
  • Autophagy
  • Autophagy-Related Protein 7
  • Caspase 8 / physiology*
  • Cell Survival
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / physiology
  • Necrosis / immunology
  • Receptor-Interacting Protein Serine-Threonine Kinases / physiology
  • T-Lymphocytes / immunology*


  • Atg7 protein, mouse
  • Microtubule-Associated Proteins
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Ripk3 protein, mouse
  • Caspase 8
  • Autophagy-Related Protein 7