Critical role for CD8 in T cell receptor binding and activation by peptide/major or histocompatibility complex multimers

Recent data using MHC/peptide tetramers and dimers suggests that the T cell coreceptors, CD4 and CD8, although important for T cell activation, do not play a direct role in facilitating T cell receptor (TCR) binding to multiv alent MHC/peptide ligands. Instead, a current model proposes that corecepto rs are recruited only after a stable TCR-MHC/peptide complex has already fo rmed and signaled. In contrast, we show using multimeric class I MHC/peptid e ligands that CD8 plays a critical tin some cases obligatory) role in anti gen-specific TCR binding. T cell activation, measured by calcium mobilizati on, was induced by multimeric but not monomeric ligands and also showed CD8 dependency. Our analysis using anti-CDS antibodies revealed that binding t o different epitopes of CD8 can either block or augment TCR-MHC/peptide int eraction. These effects on TCR binding to high-affinity agonist ligands wer e even more pronounced when binding to multimeric low-affinity ligands, inc luding TCR antagonists, was studied. Our data have important implications f or the role of CD8 in TCR binding to MHC/peptide ligands and in T cell acti vation. In addition, our results argue against the view that multimeric MHC /peptide ligands bind directly and solely to the TCR; rather, our data high light a pivotal contribution of CD8 for this association.