Abstract
A role for TNF-alpha in the pathogenesis of chronic inflammatory disease is now firmly established. Paradoxically, TNF also has potent immunomodulatory effects on CD4(+) T lymphocytes, because Ag-specific proliferative and cytokine responses are suppressed following prolonged exposure to TNF. We explored whether TNF attenuated T cell activation by uncoupling proximal TCR signal transduction pathways using a mouse T cell hybridoma model. Chronic TNF exposure induced profound, but reversible, T cell hyporesponsiveness, with TNF-treated T cells requiring TCR engagement with higher peptide concentrations for longer periods of time for commitment to IL-2 production. Subsequent experiments revealed that chronic TNF exposure led to a reversible loss of TCRzeta chain expression, in part through a reduction in gene transcription. Down-regulation of TCRzeta expression impaired TCR/CD3 assembly and expression at the cell surface and uncoupled membrane-proximal tyrosine phosphorylation events, including phosphorylation of the TCRzeta chain itself, CD3epsilon, ZAP-70 protein tyrosine kinase, and linker for activation of T cells (LAT). Intracellular Ca(2+) mobilization was also suppressed in TNF-treated T cells. We propose that TNF may contribute to T cell hyporesponsiveness in chronic inflammatory and infectious diseases by mechanisms that include down-regulation of TCRzeta expression. We speculate that by uncoupling proximal TCR signals TNF could also interrupt mechanisms of peripheral tolerance that are dependent upon intact TCR signal transduction pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / pharmacology
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Adaptor Proteins, Signal Transducing*
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Animals
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Calcium Signaling / immunology
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Carrier Proteins / metabolism
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Cell Line, Transformed
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Cell Membrane / genetics
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Clonal Deletion
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Dose-Response Relationship, Immunologic
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Down-Regulation / drug effects
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Down-Regulation / immunology*
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Humans
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Hybridomas
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Immune Tolerance / drug effects
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / biosynthesis
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / genetics
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / biosynthesis*
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Transgenic
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Phosphoproteins / metabolism
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism
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Receptor-CD3 Complex, Antigen, T-Cell / antagonists & inhibitors*
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Receptor-CD3 Complex, Antigen, T-Cell / biosynthesis*
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Receptor-CD3 Complex, Antigen, T-Cell / genetics
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Receptor-CD3 Complex, Antigen, T-Cell / metabolism
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Receptors, Antigen, T-Cell / antagonists & inhibitors*
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Receptors, Antigen, T-Cell / biosynthesis*
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / metabolism
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Recombinant Fusion Proteins / physiology
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Time Factors
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / pharmacology*
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ZAP-70 Protein-Tyrosine Kinase
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Interleukin-2
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LAT protein, human
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Lat protein, mouse
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Membrane Proteins
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Phosphoproteins
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Receptor-CD3 Complex, Antigen, T-Cell
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Receptors, Antigen, T-Cell
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Recombinant Fusion Proteins
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Tumor Necrosis Factor-alpha
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antigen T cell receptor, zeta chain
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Protein-Tyrosine Kinases
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ZAP-70 Protein-Tyrosine Kinase
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ZAP70 protein, human
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Zap70 protein, mouse
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Acetylcysteine