The role of CD4-Lck in T-cell receptor antagonism: evidence for negative signaling.
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.
Racioppi
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L
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Italy.
Matarese
G
G
D'Oro
U
U
De Pascale
M
M
Masci
A M
AM
Fontana
S
S
Zappacosta
S
S
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015704:CD4 Antigens / Q000502:physiology*; D002999:Clone Cells; D010856:Columbidae; D003574:Cytochrome c Group / Q000096:biosynthesis / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D014644:Genetic Variation; D007295:Inositol Phosphates / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008285:Major Histocompatibility Complex; D051379:Mice; D008815:Mice, Inbred Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection; D019061:src-Family Kinases / Q000502:physiology*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D003574:Cytochrome c Group; D007295:Inositol Phosphates; D007376:Interleukin-2; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases