Fast dissociation rate of peptide-MHC complexes from TCR has commonly been accepted to cause T cell anergy. In this study, we present evidence that peptides that form transient complexes with HLA-DR1 induce anergy in T cell clones in vitro and specific memory T cells in vivo. We demonstrate that similar to the low densities of long-lived agonist peptide-MHC, short-lived peptide-MHC ligands induce anergy by engagement of ∼1000 TCR and activation of a similar pattern of intracellular signaling events. These data strongly suggest that short-lived peptides induce anergy by presentation of low densities of peptide-MHC complexes. Moreover, they suggest that the traditional antagonist peptides might also trigger anergy by a similar molecular mechanism. The use of short-lived peptides to induce T cells anergy is a potential strategy for the prevention or treatment of autoimmune diseases.

Nearly 15 years of detailed investigations devoted to the understanding of the mechanism of APL function resulted in a wealth of information regarding TCR signalling at the membrane interface and the nature of intracellular signalling molecules. All studied antagonist and partial agonist peptide variants were thought to have identical anchor residues to the agonist peptides, and hence form stable complexes with MHC molecules. Thus it was logical to assume that their differences from the agonist must