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The caspase 8 inhibitor c-FLIP(L) modulates T-cell receptor-induced proliferation but not activation-induced cell death of lymphocytes.
Molecular and Cellular Biology
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.
Animals, Antigens, CD3/pharmacology, Antigens, CD4/biosynthesis, Antigens, CD45/metabolism, Antigens, CD8/biosynthesis, Apoptosis/drug effects, CASP8 and FADD-Like Apoptosis Regulating Protein, Carrier Proteins/genetics, Carrier Proteins/metabolism, Caspase 8, Caspase 9, Caspases/antagonists & inhibitors, Caspases/metabolism, Cell Division/drug effects, Cell Division/physiology, Cells, Cultured, Enzyme Inhibitors/metabolism, Enzyme Inhibitors/pharmacology, Fas Ligand Protein, Flow Cytometry, Humans, Interleukin-2/biosynthesis, Intracellular Signaling Peptides and Proteins, Lymphocyte Activation/drug effects, Lymphocyte Activation/physiology, Macromolecular Substances, Membrane Glycoproteins/pharmacology, Mice, Mice, Inbred Strains, Mice, Transgenic, Protein Isoforms/metabolism, Protein Isoforms/pharmacology, Receptors, Antigen, T-Cell/metabolism, T-Lymphocytes/cytology, T-Lymphocytes/drug effects
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