Immune discrimination of self and nonself: A unified theory for the induction of self tolerance among thymocytes and mature peripheral T cells

Abstract

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 and 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.