EARLY BIOCHEMICAL SIGNALS ARISE FROM LOW-AFFINITY TCR-LIGAND REACTIONS AT THE CELL-CELL INTERFACE

The kinetics of acid release by a mixture of T cells and antigen prese nting cells were measured with a microphysiometer during a brief expos ure to antigenic peptides. We find that some of the early biochemical events that lead to cellular proliferation cause a specific increase i n the rate of acid release. The duration of this increase in acid rele ase reflects the life-time of the peptide-MHC complexes. Peptides that form long-lived complexes product a response that is stable for more than an hour. Serial TCR engagement is suggested by the observation th at die amplitude of this stable response can be rapidly shifted up or down with additional agonist peptide or with antibodies that block T c ell receptor binding. Cells briefly exposed to a peptide that forms sh ort-lived peptide-MHC complexes produce a response that decays rapidly as peptide is washed away. A quantitative analysis of the kinetics of this decay in acidification demonstrates that intercellular TCR-ligan d reactions are rapid, reversible, and of low apparent affinity with < 20% of peptide-MHC ligand bound to a TCR at any one time. These result s demonstrate that the fraction of peptide-MHC ligands bound to TCRs a t the cell-cell interface is no higher than anticipated from the affin ities observed in solution for isolated TCRs and ligands.