A unified model for T cell antigen recognition and thymic selection of the T cell repertoire

Abstract

Positive selection of T cells during thymic differentiation predisposes mature T cells to recognize glycoproteins encoded by "self" alleles of the major histocompatibility complex (MHC) as "restricting elements" for antigen presentation. Yet, negative selection also occurs during thymic differentiation resulting in the clonal deletion of T cells reactive with "self" MHC glycoproteins. Thymic processes of positive and negative selection represent a paradox because the "altered self" view of T cell receptor (TcR) recognition indicates that the same type of TcR-MHC glycoprotein binding interaction mediates both positive and negative selection of the T cell repertoire. Most contemporary models of thymic selection attempt to explain these paradoxical observations by quantitative differences of affinity. That is, TcR interactions with MHC ligands that are of medium affinity lead to positive selection whereas those that are of high affinity lead to negative selection. The purpose of this manuscript is to provide an alternative model of thymic selection based on the efficacy (the ability of a ligand to catalyze receptor mediated biological activity) of TcR-MHC ligand interactions. The "efficacy" model predicts that among those thymocytes exhibiting affinity for self MHC ligands, some clones bind self MHC ligands without efficacy whereas others bind these ligands with efficacy. Immature T cells that bind MHC ligands without efficacy do not undergo TcR mediated activation and thereby escape clonal deletion. Instead, these T cells compete for growth--promoting sites on thymic antigen presenting cells (APC) based upon their clonotypic TcR affinity for self MHC ligands. These T cells experience positive thymic selection and eventually dominate a repertoire of mature T cells predisposed to exhibit non-efficacious binding to "self" MHC ligands. In contrast, immature T cells that exhibit efficacious binding to self MHC ligands are deleted from the T cell repertoire during thymic maturation. By this mechanism, the mature T cell repertoire is selected so that clonotypic T cells are predisposed to bind the very sites on MHC glycoproteins responsible for antigen presentation without risk of autoimmunity. Given the clonotypic diversity of the mature repertoire, complexes of foreign peptides and self MHC glycoproteins would be recognized by clones of the appropriate specificity as highly efficacious ligands. In summary, the "efficacy" model is entirely consistent with the "altered self" concept of T cell antigen recognition and readily accounts for both positive and negative selection of the T cell repertoire.