Abstract
The caspase 8 inhibitor c-FLIP(L) can act in vitro as a molecular switch between cell death and growth signals transmitted by the death receptor Fas (CD95). To elucidate its function in vivo, transgenic mice were generated that overexpress c-FLIP(L) in the T-cell compartment (c-FLIP(L) Tg mice). As anticipated, FasL-induced apoptosis was inhibited in T cells from the c-FLIP(L) Tg mice. In contrast, activation-induced cell death of T cells in c-FLIP(L) Tg mice was unaffected, suggesting that this deletion process can proceed in the absence of active caspase 8. Accordingly, c-FLIP(L) Tg mice differed from Fas-deficient mice by showing no accumulation of B220(+) CD4(-) CD8(-) T cells. However, stimulation of T lymphocytes with suboptimal doses of anti-CD3 or antigen revealed increased proliferative responses in T cells from c-FLIP(L) Tg mice. Thus, a major role of c-FLIP(L) in vivo is the modulation of T-cell proliferation by decreasing the T-cell receptor signaling threshold.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CD3 Complex / pharmacology
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CD4 Antigens / biosynthesis
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CD8 Antigens / biosynthesis
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Carrier Proteins / pharmacology
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Caspase 8
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Caspase 9
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Caspase Inhibitors*
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Caspases / metabolism
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Cell Division / drug effects
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Cell Division / physiology
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Cells, Cultured
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Enzyme Inhibitors / metabolism*
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Enzyme Inhibitors / pharmacology
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Fas Ligand Protein
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Flow Cytometry
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Humans
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Interleukin-2 / biosynthesis
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Intracellular Signaling Peptides and Proteins*
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Leukocyte Common Antigens / metabolism
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / physiology
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Macromolecular Substances
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Membrane Glycoproteins / pharmacology
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Mice
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Mice, Inbred Strains
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Mice, Transgenic
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Protein Isoforms / metabolism
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Protein Isoforms / pharmacology
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Receptors, Antigen, T-Cell / metabolism*
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism*
Substances
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CD3 Complex
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CD4 Antigens
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CD8 Antigens
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CFLAR protein, human
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Carrier Proteins
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Caspase Inhibitors
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Cflar protein, mouse
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Enzyme Inhibitors
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Interleukin-2
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Intracellular Signaling Peptides and Proteins
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Macromolecular Substances
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Membrane Glycoproteins
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Protein Isoforms
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Receptors, Antigen, T-Cell
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Leukocyte Common Antigens
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CASP8 protein, human
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CASP9 protein, human
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Casp8 protein, mouse
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Casp9 protein, mouse
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Caspase 8
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Caspase 9
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Caspases