Fully competent dendritic cells as inducers of T cell anergy in autoimmunity

Mature immunologically competent dendritic cells are the most efficient antigen presenting cells, that powerfully activate T cells and initiate and sustain immune responses. Indeed, dendritic cells are able to efficiently capture antigens, express high levels of co-stimulatory molecules and produce the combination of cytokines required to create a powerful immune response. They are also considered to be important in initiating autoimmune disease by efficiently presenting autoantigens to self-reactive T cells that, in this case, will mount a pathogenic autoimmune reaction. Triggering T cells is not a simple on-off procedure, as TCR responds to minor changes in ligand with gradations of T-cell activation and effector functions. These 'misfit' peptides have been called Altered Peptide Ligands, and have been shown to have important biological significance. Here we show that fully capable dendritic cells may present, upon natural antigen processing, a self-epitope with Altered Peptide Ligands features that can unexpectedly induce anergy in a human autoreactive T cell clone. These results indicate that presentation of a self-epitope by immunologically competent dendritic cells does not always mean 'danger' and show a novel mechanism involved in the fine balance between T cell activation and tolerance induction in man.