INITIATION OF SIGNAL-TRANSDUCTION THROUGH THE T-CELL RECEPTOR REQUIRES THE PEPTIDE MULTIVALENT ENGAGEMENT OF MHC LIGANDS

While much is known about intracellular signaling events in T cells wh en T cell receptors (TCRs) are engaged, the mechanism by which signali ng is initiated is unclear. We have constructed defined oligomers of s oluble antigen-major histocompatibility complex (MHC) molecules, the n atural ligands for the TCR. Using these to stimulate specific T cells in vitro, we find that agonist peptide/MHC ligands are nonstimulatory as monomers and minimally stimulatory as dimers. Similarly, a partial- agonist ligand is very weakly active as a tetramer. In contrast, trime ric or tetrameric agonist ligands that engage multiple TCRs for a sust ained duration are potent stimuli. Ligand-driven formation of TCR clus ters seems required for effective activation and helps to explain the specificity and sensitivity of T cells.