The role of CD4-Lck in T-cell receptor antagonism: evidence for negative signaling

Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10360-5. doi: 10.1073/pnas.93.19.10360.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal
  • Antigen-Presenting Cells / immunology*
  • CD4 Antigens / physiology*
  • Clone Cells
  • Columbidae
  • Cytochrome c Group / biosynthesis
  • Cytochrome c Group / immunology
  • Cytotoxicity, Immunologic
  • Genetic Variation
  • Inositol Phosphates / metabolism
  • Interleukin-2 / biosynthesis
  • Lymphocyte Activation
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Major Histocompatibility Complex
  • Mice
  • Mice, Inbred Strains
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Sequence Data
  • Nerve Tissue Proteins / metabolism
  • Peptide Fragments / chemistry
  • Peptide Fragments / immunology
  • Peptide Fragments / pharmacology
  • Receptors, Antigen, T-Cell / biosynthesis
  • Receptors, Antigen, T-Cell / physiology*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / immunology
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*
  • Transfection
  • src-Family Kinases / physiology*


  • Antibodies, Monoclonal
  • CD4 Antigens
  • Cytochrome c Group
  • Inositol Phosphates
  • Interleukin-2
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • src-Family Kinases
  • Mitogen-Activated Protein Kinases