The peptidic self model: a reassessment of the role of the major histocompatibility complex molecules in the restriction of the T-cell response

Abstract

After having proposed, with the "peptidic self model", that class I or class II molecules of the major histocompatibility complex (MHC) expose peptides derived from self proteins on the surface of most somatic cells (as they do for foreign protein on the surface of macrophages, dendritic cells and B cells), we review here some of the recent evidence which suggests that the presentation of self or non-self peptides is strongly selected by the self-MHC molecules, in terms of amino acid sequence and possibly by three-dimensional conformation. On this basis, we further propose that T-cell receptors specifically recognize the exposed peptides, to the exclusion of the polymorphic parts of self-MHC molecules. Thus, the presentation of the antigen rather than its recognition by T cell would be "MHC-restricted". We show that such an inversion of perspective by which MHC molecules are seen as "peptide receptors" of degenerate specificity rather than "self markers" can provide, in the framework of the "peptidic self model", the basis for a consistent theory of self/non-self discrimination, alloreactivity and the ontogeny of the T-cell repertoire.