Abstract
Fas-associated death domain (FADD) is a death domain containing cytoplasmic adapter molecule required for the induction of apoptosis by death receptors. Paradoxically, FADD also plays a crucial role in the development and proliferation of T cells. Using T cells from mice expressing a dominant negative form of FADD (FADDdd), activation with anti-TCR Ab and costimulation or exogenous cytokines is profoundly diminished. This is also seen in wild-type primary T cells transduced with the same transgene, demonstrating that FADD signaling is required in normally differentiated T cells. The defective proliferation does not appear to be related to the early events associated with TCR stimulation. Rather, with a block in FADD signaling, stimulated T cells exhibit a high rate of cell death corresponding to the initiation of cell division. Although CD4 T cells exhibit a moderate deficiency, this effect is most profound in CD8 T cells. In vivo, the extent of this defective accumulation is most apparent; lymphocytic choriomenigitis virus-infected FADDdd-expressing mice completely fail to mount an Ag-specific response. These results show that, in a highly regulated fashion, FADD, and most likely caspases, can transduce either a signal for survival or one that leads directly to apoptosis and that the balance between these opposing outcomes is crucial to adaptive immunity.
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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Adaptor Proteins, Signal Transducing*
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Animals
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Apoptosis / genetics
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Apoptosis / immunology*
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CD4-CD8 Ratio
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / virology
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Cell Death / genetics
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Cell Death / immunology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Division / genetics
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Cell Division / immunology
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Cell Line
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Cell Survival / genetics
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Cell Survival / immunology
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Cells, Cultured
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Epitopes, T-Lymphocyte / genetics
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Epitopes, T-Lymphocyte / immunology
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Fas-Associated Death Domain Protein
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Humans
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Lymphocytic Choriomeningitis / genetics
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Lymphocytic Choriomeningitis / immunology
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Lymphocytic Choriomeningitis / pathology
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Lymphocytic Choriomeningitis / virology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Retroviridae / genetics
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocyte Subsets / cytology*
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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Transduction, Genetic
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Transgenes / immunology
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Up-Regulation / genetics
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Up-Regulation / immunology
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fas Receptor / genetics
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fas Receptor / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Epitopes, T-Lymphocyte
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FADD protein, human
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Fadd protein, mouse
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Fas-Associated Death Domain Protein
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fas Receptor