Apoptosis and T-cell repertoire selection in the thymus.

Thymic tolerance depends on induction of apoptosis (programmed cell death) in immature thymocytes by antigen/MHC complexes on dendritic cells (and possibly other bone marrow-derived APCs). Interactions with antigen/MHC complexes on thymic epithelial cells promote maturation of double-positive thymocytes to single-positive cells. However, the nature of the antigen/MHC complexes on thymic epithelial cells is unknown, and if the stromal cell interaction model as just outlined is correct, then presumably these complexes must be different from those presented on dendritic cells, otherwise all cells signaled for positive selection would be subject to negative selection by similar complexes on APCs. The nature of the signals provided by thymic epithelial cells versus dendritic cells is unknown and may provide a key to understanding the processes of positive and negative selection within the thymus. Clearly the intense selection of the T-cell repertoire within the thymus explains the high level of cell death observed within the immature thymocyte compartment. Such intensive selection shapes the T-cell repertoire in a way that provides an explanation for the genetic basis of immune responsiveness and for the susceptibility of certain individuals to autoimmunity.