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 m ajor histocompatibilty complex generate ligands able to partially acti vate (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 inos itol phospholipid hydrolysis and extracellular regulated kinase activa tion, exposure of a T-cell clone to increasing antagonist concentratio ns increased the activity of the CD4-Lck kinase. Addition of anti-CD4 antibody to culture medium prevented inhibitory effects induced by ant agonist ligand, We propose that CD4-Lck activation triggered by antago nist complexes may act in a dominant negative mode, thus overriding st imulatory 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 activitie s or trigger alternative activation programs.