Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity
- Leonardo Salmena1,2,3,
- Benedicte Lemmers1,2,3,
- Anne Hakem1,2,3,
- Elzbieta Matysiak-Zablocki1,2,3,
- Kiichi Murakami2,3,
- P.Y. Billie Au1,2,3,
- Donna M. Berry3,4,
- Laura Tamblyn1,2,3,
- Amro Shehabeldin1,2,3,
- Eva Migon1,2,3,
- Andrew Wakeham1,2,
- Denis Bouchard1,2,
- Wen Chen Yeh1,2,3,
- Jane C. McGlade3,4,
- Pamela S. Ohashi2,3, and
- Razqallah Hakem1,2,3,5
Abstract
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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Footnotes
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↵5 Corresponding author.
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E-MAIL rhakem{at}uhnres.utoronto.ca; FAX (416) 204-2277.
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Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1063703.
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- Received December 2, 2002.
- Accepted February 18, 2003.
- Cold Spring Harbor Laboratory Press