Self peptides and the peptidic self

Twenty years ago, antigenic and self peptides presented by MHC molecules were absent from the immunological scene. While foreign peptides could be assayed by immune reactions, self peptides, as elusive and invisible as they were at the time, were bound to have an immunological role. How self peptides are selected and presented by MHC molecules, and how self MHC-peptide complexes are seen or not seen by T cells raised multiple questions particularly related to MHC restriction, alloreactivity, positive and negative selection, the nature of tumor antigens and tolerance. These issues were addressed in the "peptiditic self model" (1986) and subsequent hypothesis. They are retrospectively and critically reviewed here in the context of our current understanding of these major immunological phenomena.