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Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity

  • Leonardo Salmena
  • Benedicte Lemmers
  • Anne Hakem
  • Elzbieta Matysiak-Zablocki
  • Kiichi Murakami
  • P.Y. Billie Au
  • Donna M. Berry
  • Laura Tamblyn
  • Amro Shehabeldin
  • Eva Migon
  • Andrew Wakeham
  • Denis Bouchard
  • Wen Chen Yeh
  • Jane C. McGlade
  • Pamela S. Ohashi
  • Razqallah Hakem
Cold Spring Harbor Laboratory Press
Publication Date
Apr 01, 2003
  • Medicine


Defects in death receptor-mediated apoptosis have been linked to cancer and autoimmune disease in humans. The in vivo role of caspase 8, a component of this pathway, has eluded analysis in postnatal tissues because of the lack of an appropriate animal model. Targeted disruption of caspase 8 is lethal in utero. We generated mice with a targeted caspase 8 mutation that is restricted to the T-cell lineage. Despite normal thymocyte development in the absence of caspase 8, we observed a marked decrease in the number of peripheral T-cells and impaired T-cell response ex vivo to activation stimuli. caspase 8 ablation protected thymocytes and activated T-cells from CD95 ligand but not anti-CD3-induced apoptosis, or apoptosis activated by agents that are known to act through the mitochondria. caspase 8 mutant mice were unable to mount an immune response to viral infection, indicating that caspase 8 deletion in T-cells leads to immunodeficiency. These findings identify an essential, cell-stage-specific role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. This is consistent with the recent identification of caspase 8 mutations in human immunodeficiency.

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