Linkage of immune self-tolerance with the positive selection of T cells.

Development and maturation of antigen-specific T cells take place in the thymus in a process dependent on recognition by the T cell antigen receptor (TCR) of endogenous self-peptides presented by several types of specialized stromal cells. Paradoxically, emerging T cells are not self-reactive, and it is commonly believed that deletion of high avidity autoreactive T cells is the principal mechanism for establishing self-tolerance. However, there is increasing evidence that the positive selection of T cells on self-peptides presented by thymic cortical epithelial cells must be linked with a process that prevents their subsequent activation when the same self-peptides are encountered in the periphery. Consequently, a higher activation threshold is established that can be overcome only with ligands of higher affinity, which would normally be foreign peptides. The molecular basis for this increase in activation threshold is unknown, but observations on differential signaling by peptide analogs, on increased TCR expression during T cell maturation and on energy induction in the absence of costimulation provide promising leads. Linkage of self-tolerance with positive selection is a simple and evolutionary sound explanation for self/non-self discrimination and offers a framework for understanding systemic autoimmunity.