Abstract
Small changes in the complex between a peptide and a molecule of the major histocompatibility complex generate ligands able to partially activate (partial agonist) or even inhibit (antagonist) T-cell functions. T-cell receptor engagement of antagonist complex results in a partial zeta chain phosphorylation without activation of the associated ZAP-70 kinase. Herein we show that, despite a strong inhibition of both inositol phospholipid hydrolysis and extracellular increasing antagonist concentrations increased the activity of the CD4-Lck kinase. Addition of anti-CD4 antibody to culture medium prevented inhibitory effects induced by antagonist ligand. We propose that CD4-Lck activation triggered by antagonist complexes may act in a dominant negative mode, thus overriding stimulatory signals coming from agonist ligand. These findings identify a new T-cell signaling profile that may explain the ability of some T-cell receptor variant ligands to inhibit specific biological activities or trigger alternative activation programs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Antibodies, Monoclonal
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Antigen-Presenting Cells / immunology*
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CD4 Antigens / physiology*
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Clone Cells
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Columbidae
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Cytochrome c Group / biosynthesis
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Cytochrome c Group / immunology
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Cytotoxicity, Immunologic
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Genetic Variation
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Inositol Phosphates / metabolism
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Interleukin-2 / biosynthesis
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Lymphocyte Activation
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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Major Histocompatibility Complex
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Mice
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Mice, Inbred Strains
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Mitogen-Activated Protein Kinases / metabolism
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Molecular Sequence Data
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Nerve Tissue Proteins / metabolism
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Peptide Fragments / chemistry
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Peptide Fragments / immunology
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Peptide Fragments / pharmacology
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Receptors, Antigen, T-Cell / biosynthesis
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Receptors, Antigen, T-Cell / physiology*
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / immunology
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Signal Transduction / immunology
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T-Lymphocytes / immunology*
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Transfection
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src-Family Kinases / physiology*
Substances
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Antibodies, Monoclonal
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CD4 Antigens
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Cytochrome c Group
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Inositol Phosphates
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Interleukin-2
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Nerve Tissue Proteins
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Peptide Fragments
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Receptors, Antigen, T-Cell
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Recombinant Proteins
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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src-Family Kinases
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Mitogen-Activated Protein Kinases