Open AccessThe role of CD4-Lck in T-cell receptor antagonism: evidence for negative signaling.
Author(s) -
Anthony Means,
Giuseppe Matarese,
Ugo D’Oro,
Mariano Pascale,
Anna Maria Masci,
Silvia Fontana,
Serafino Zappacosta
Publication year - 1996
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.93.19.10360
Subject(s) - antagonist , partial agonist , microbiology and biotechnology , agonist , receptor , antagonism , signal transduction , t cell receptor , competitive antagonist , chemistry , t cell , biology , biochemistry , immunology , immune system
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.