SELF DETERMINANT SELECTION AND ACQUISITION OF THE AUTOIMMUNE T-CELL REPERTOIRE

Autologous proteins are continuously processed and presented in the fo rm of peptides associated with self major histocompatibility (MHC) mol ecules at the surface of antigen-presenting cells for interaction with autoreactive T cells. During thymic selection, the presentation of se lf peptides is an essential element in the establishment of the T cell repertoire. Developing T cells which recognize self peptide/self MHC complexes with sufficient affinity are clonally deleted. However, we a nd others have recently demonstrated that a variety of self peptides, despite their high binding affinity to MHC molecules, never reach the threshold of presentation to ensure negative selection (cryptic self p eptides). This mechanism may have been selected to avoid excessive pur ging of T cell repertoire during ontogeny. However, T cells directed t o cryptic self determinants represent a continuous threat for the init iation of autoimmunity in adults. Supporting this view, recent studies have documented the involvement of cryptic self peptide presentation in different autoimmune diseases. In this article. We examine the fact ors that govern the selection of self peptides for presentation to aut oreactive T cells in vivo and discuss their contribution to both the i nduction and the maintenance of self tolerance. In addition, we analyz e the mechanisms by which the hierarchy of determinants on a self prot ein can be disrupted, thereby leading to the presentation of previousl y cryptic self peptides and the induction of an autoimmune T-cell-medi ated process.