title: Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity.
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.
authors.affiliation: The Advanced Medical Discovery Institute (AMDI), Ontario Cancer Institute, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salmena
authors.forename: Benedicte
authors.initials: B
authors.lastname: Lemmers
authors.forename: Anne
authors.initials: A
authors.lastname: Hakem
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Matysiak-Zablocki
authors.forename: Kiichi
authors.initials: K
authors.lastname: Murakami
authors.forename: P Y Billie
authors.initials: PY
authors.lastname: Au
authors.forename: Donna M
authors.initials: DM
authors.lastname: Berry
authors.forename: Laura
authors.initials: L
authors.lastname: Tamblyn
authors.forename: Amro
authors.initials: A
authors.lastname: Shehabeldin
authors.forename: Eva
authors.initials: E
authors.lastname: Migon
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Denis
authors.initials: D
authors.lastname: Bouchard
authors.forename: Wen Chen
authors.initials: WC
authors.lastname: Yeh
authors.forename: Jane C
authors.initials: JC
authors.lastname: McGlade
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Razqallah
authors.initials: R
authors.lastname: Hakem
mesh_terms: 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
chemical_list: 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