Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity.
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.
Salmena
Leonardo
L
The Advanced Medical Discovery Institute (AMDI), Ontario Cancer Institute, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
Lemmers
Benedicte
B
Hakem
Anne
A
Matysiak-Zablocki
Elzbieta
E
Murakami
Kiichi
K
Au
P Y Billie
PY
Berry
Donna M
DM
Tamblyn
Laura
L
Shehabeldin
Amro
A
Migon
Eva
E
Wakeham
Andrew
A
Bouchard
Denis
D
Yeh
Wen Chen
WC
McGlade
Jane C
JC
Ohashi
Pamela S
PS
Hakem
Razqallah
R
D000818:Animals; D001483:Base Sequence; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D017931:DNA Primers; D018274:Electroporation; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006706:Homeostasis; D007111:Immunity, Cellular / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D013937:Thymidine Kinase / Q000235:genetics
D017931:DNA Primers; D013937:Thymidine Kinase; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases