Using thymus anatomy to dissect T cell repertoire selection

The thymic development of CD4(+) T cells incorporates the opposing processe s of positive and negative selection to produce mature lymphocytes which re spond to foreign pep tides in the context of self-major histocompatibility complex class II molecules. Here, we present a model in which these events occur in two temporally and anatomically distinct steps. Mie propose that a n initial positive selection step is mediated exclusively by thymic cortica l epithelium. Subsequently, all those thymocytes which have been positively selected will interact with medullary epithelium and bone marrow-derived c ells. Those thymocytes reacting with excess affinity or avidity to these an tigen presenting cells will be negatively selected. Although acknowledging the importance of differential sig-nailing to the developing thymocyte, we will emphasize the centrality of the phenotype of the tissues which compris e the thymus.