Abstract
4-1BB is a member of the TNFR superfamily expressed on activated CD4+ and CD8+ T cells. 4-1BB can costimulate IL-2 production by resting primary T cells independently of CD28 ligation. In this study, we report signaling events following 4-1BB receptor aggregation using an Ak-restricted costimulation-dependent T cell hybridoma, C8.A3. Aggregation of 4-1BB on the surface of C8.A3 cells induces TNFR-associated factor 2 recruitment, which in turn recruits and activates apoptosis signal-regulating kinase-1, leading to downstream activation of c-Jun N-terminal/stress-activated protein kinases (JNK/SAPK). 4-1BB ligation also enhances anti-CD3-induced JNK/SAPK activation in primary T cells. Overexpression of a catalytically inactive form of apoptosis signal-regulating kinase-1 in C8.A3 T cells interferes with activation of the SAPK cascade and with IL-2 secretion, consistent with a critical role for JNK/SAPK activation in 4-1BB-dependent IL-2 production. Given the ability of both CD28 and 4-1BB to induce JNK/SAPK activation, we asked whether hyperosmotic shock, another inducer of this cascade, could function to provide a costimulatory signal to T cells. Osmotic shock of resting primary T cells in conjunction with anti-CD3 treatment was found to costimulate IL-2 production by the T cells, consistent with a pivotal role for JNK/SAPK in T cell costimulation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD
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Calcium-Calmodulin-Dependent Protein Kinases / physiology*
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Enzyme Activation / immunology
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Hybridomas / enzymology
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Hybridomas / immunology
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Hybridomas / metabolism
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Interleukin-2 / biosynthesis
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JNK Mitogen-Activated Protein Kinases
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Lymphocyte Activation
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MAP Kinase Kinase Kinase 5
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MAP Kinase Kinase Kinases*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinases*
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Osmotic Pressure
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Protein Serine-Threonine Kinases / metabolism
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Proteins / metabolism
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Receptor Aggregation / immunology
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Receptors, Nerve Growth Factor / immunology
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Receptors, Nerve Growth Factor / metabolism
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Receptors, Nerve Growth Factor / physiology*
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Receptors, Tumor Necrosis Factor / immunology
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Receptors, Tumor Necrosis Factor / metabolism
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Receptors, Tumor Necrosis Factor / physiology*
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Signal Transduction / immunology*
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T-Lymphocytes / enzymology*
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor Receptor Superfamily, Member 9
Substances
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Antigens, CD
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Interleukin-2
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Proteins
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Receptors, Nerve Growth Factor
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Receptors, Tumor Necrosis Factor
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TNF Receptor-Associated Factor 2
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Tnfrsf9 protein, mouse
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 5
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MAP Kinase Kinase Kinases
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Map3k5 protein, mouse