IMMUNE DISCRIMINATION OF SELF AND NONSELF - A UNIFIED THEORY FOR THE INDUCTION OF SELF TOLERANCE AMONG THYMOCYTES AND MATURE PERIPHERAL T-CELLS

A comprehensive model of immunological self tolerance is described which is based on the unique tenet that interactions between T cell antigen receptors (TcR) and specific MHC ligands may vary in efficacy (the ability of an MHC ligand to catalyze TcR-mediated activation). Based on this postulate, two interrelated mechanisms are described to explain how self tolerance is induced among immature thymocytes and mature peripheral T cells, respectively. In the thymus, APC apparently present a diverse array of self MHC ligands (complexes of self peptides and MHC glycoproteins) to clonotypic T cells. According to the first mechanism, immature thymocytes that efficaciously bind specific MHC ligands undergo TcR-mediated activation and programmed cell death whereas those that nonefficaciously bind MHC ligands are not activated and thereby escape negative selection. The latter T cells undergo positive selection and eventually constitute the mature T cell repertoire. This model of thymic selection ensures that interactions of mature T cells with self in peripheral tissues are predominantly nonefficacious. According to the second mechanism, clonotypically diverse T cells and individual APC comprise an integrative unit that measures antigenic complexity of the local environment as a basis to enable or disable immunogenic responses by mature T cells. T cells recognize efficacious MHC ligands (E) via the TcR/ CD3 complex but are also able to detect nonefficacious MHC ligands (N) by conserved signal transduction pathways that are initiated upon cell-cell contact with APC. Clonotypic T cells relay E or N signals by conserved feedback pathways back to APC. APC integrate and compare large numbers of E or N signals to derive an E/ N ratio. The abrupt appearance of antigenically complex entities that were exempted from thymic selection (infectious agents or foreign entities) induces relatively high E/ N ratios which in turn elicit expression of co-stimulatory signals. Exclusive presentation of self by APC results in relatively low E/ N ratios which in turn suppress co-stimulatory signalling pathways. Recognition of efficacious MHC ligands in the presence or absence of co-stimulatory signals leads to either responsiveness or tolerance, respectively. Thus, this model predicts that T cells are selected in the thymus and periphery to nonefficaciously recognize self and are only elicited upon the predominantly efficacious recognition of a diversity of nonself determinants.